Pyrrolo[1,2-b] pyridazine derivatives

ABSTRACT

A compound of Formula (I): 
                         
pharmaceutically acceptable salts thereof, deuterated analogs thereof, compositions thereof, and methods of treating disease using a compound thereof, wherein the variable substituents are disclosed herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of U.S. Ser. No. 16/508,979, filed 11Jul. 2019, now U.S. Pat. No. 10,875,866, the disclosure of which ishereby incorporated by reference.

FIELD

The present disclosure relates to novel compounds that are inhibitors ofthe kinase IRAK4. The disclosure also relates to methods for preparingthe compounds and to pharmaceutical compositions comprising suchcompounds.

BACKGROUND

Interleukin-1 receptor-associated kinase-4 (IRAK4) is a serine-threoninekinase which acts as a mediator in interleukin-1/Toll-like receptor(IL-1/TLR) signaling cascades. More particularly, IRAK4 is involved inactivation of adaptor protein myeloid differentiation primary responsegene 88 (MyD88) signaling cascades and is hypothesized to play a role ininflammatory and fibrotic disorders, such as rheumatoid arthritis (RA),inflammatory bowel disease (IBD), gout, Lyme disease, arthritis,psoriasis, pelvic inflammatory disease, systemic lupus erythematosus(SLE), Sjogren's syndrome, viral myocarditis, acute and chronic tissueinjury, non-alcoholic steatohepatitis (NASH), alcoholic hepatitis andkidney disease, including chronic kidney disease and diabetic kidneydisease. In addition, IRAK4 plays a role in certain cancers and ishypothesized to play a role in inflammation associated withgastrointestinal infections, including C. difficile. Signaling throughIL-1R/TLR results in the activation of MyD88 which recruits IRAK4 andIRAK1 to form a signaling complex. This complex then interacts with aseries of kinases, adaptor proteins, and ligases, ultimately resultingin the activation of nuclear factor kappa-light-chain-enhancer ofactivated B cells (NF-κB), activator protein-1 (API), cyclicAMP-responsive element-binding protein (CREB) and theinterferon-regulatory factors (IRFs), including IRF5 and IRF7, inducingthe generation of pro-inflammatory cytokines and type I interferons.

Therefore, inhibitors of IRAK4 may be useful in the treatment ofinflammatory and fibrotic disorders, such as rheumatoid arthritis (RA),inflammatory bowel disease (IBD), gout, Lyme disease, arthritis,psoriasis, pelvic inflammatory disease, systemic lupus erythematosus(SLE), Sjogren's syndrome, inflammation associated with gastrointestinalinfections, including C. difficile, viral myocarditis, acute and chronictissue injury, non-alcoholic steatohepatitis (NASH), alcoholic hepatitisand kidney disease, including chronic kidney disease and diabetic kidneydisease. (Joosten, L. A. B et al., TOLL-LIKE RECEPTORS AND CHRONICINFLAMMATION IN RHEUMATIC DISEASES: NEW DEVELOPMENTS, Nat. Rev.Rheumatol., 346|Jun. 2016 12; 344-357 Published online 12 May 2016)(Valaperti, A. et al., INNATE IMMUNE INTERLEUKIN-1RECEPTOR-ASSOCIATEDKINASE 4 EXACERBATES VIRAL MYOCARDITIS BY REDUCING CCR5⁺CD11b⁺ MONOCYTEMIGRATION AND IMPAIRING INTERFERON PRODUCTION, Circulation, 128|Sep.2013 14; 1542-1554), as well as Type I interferonopathies, such asAicardi-Goutières syndrome, Familial chilblain lupus, and Retinalvasculopathy with cerebral leukodystrophy, (Lee-Kirsch et al., TYPE IINTERFERONOPATHIES—AN EXPANDING DISEASE SPECTRUM OF IMMUNODYSREGULATION,Semin. Immunopathol. (2015) 37:349-357), (Leaf, L A. et al., PERICYTEMYD88 AND IRAK4 CONTROL INFLAMMATORY AND FIBROTIC RESPONSES TO TISSUEINJURY, The Journal of Clinical Investigation, 127|Jan. 2017 1;321-334), (Seki, E. et al., TLR4 ENHANCES TGF-β SIGNALING AND HEPATICFIBROSIS, Nature Medicine, 13|Nov. 2007 11; 1324-1332),(Garcia-Martinez, I. et al., HEPATOCYTE MITOCHONDRIAL DNA DRIVESNONALCHOLIC STEATOHEPATITIS BY ACTIVATION OF TLR9, The Journal ofClinical Investigation, 126|Mar. 2016 3; 859-864).

In addition, certain cancers, including lymphomas, may contain one ormore mutations in the MYD88 adaptor protein, leading to a constitutivelyactive signaling cascade that may promote survival of tumor cells.(Kelly et al., IRAK4 inhibitors for autoimmunity and lymphoma, J. Exp.Med. 2015 Vol. 212 No. 13 2189-2201)

Therefore, an inhibitor of IRAK4 may be useful in the treatment ofcancers, including lymphomas.

There are currently no approved IRAK4 inhibiting pharmaceuticals.Therefore, it would be useful to provide an IRAK4 inhibiting compoundwith properties suitable for administration as a pharmaceutical agent toa mammal, particularly a human. Considerations for selecting apharmaceutical compound are multifactorial. Compound characteristicsincluding on-target potency, pharmacokinetics, pKa, solubility,stability (e.g., metabolic stability) and off-target liabilities(including potential cardiac toxicity), as well as potential drug-druginteractions are frequently profiled.

Inhibition of the cardiac ion channel coded by humanether-à-gogo-related gene (hERG) can lead to cardiac arrhythmia, whichis a major concern in drug discovery and development. Automatedelectrophysiological patch clamp allows assessment of hERG channeleffects early in drug development to aid medicinal chemistry programsand has become routine in pharmaceutical companies. Early identificationof hERG liability in drug discovery programs by automated patch clamp,Front Pharmaco. (2 Sep. 2014); 5: 203.

WO2016210034, WO2016210036, WO2015150995, WO2016127024, and WO2016210037recite compounds said to be useful as IRAK4 inhibitors.

SUMMARY OF THE INVENTION

Provided herein are compounds and pharmaceutical compositions useful asinhibitors of IRAK4. Some compounds of the disclosure may find use inpharmaceutical compositions, together with at least one pharmaceuticallyacceptable excipient, for treating a subject in need thereof. Compoundsof the present disclosure also have been found to inhibit production ofpro-inflammatory cytokines TNFα, IL-6, IL-1β, IL-8, IL-12, IL-23 andtype I interferons IFNα and IFNβ, all of which are mediators ofinflammation and the immune response. The disclosure also providescompositions, including pharmaceutical compositions, kits that includethe compounds, and methods of using and making the compounds.

In one embodiment of the disclosure, there is provided a compound ofFormula (I):

or a pharmaceutically acceptable salt or structural isomer thereof,wherein:

R¹ is selected from H, deuterium or C₁₋₄alkyl, and said C₁₋₄alkyl isoptionally substituted with one or more halo;

R² is selected from H, deuterium or C₁₋₄alky, and said alkyl isoptionally substituted with one or more halo; or

R¹ and R², together with the carbon atoms to which they are attached,form a C3-C6 cycloalkyl; and

R³ is C₀₋₄alkyl-CN.

In an embodiment, R² is H.

In an embodiment, R¹ is methyl.

In an embodiment, R³ is —CN.

In another embodiment there is provided a compound of Formula II:

or a pharmaceutically acceptable salt or structural isomer thereof,wherein:

R¹ is selected from H, deuterium or C₁₋₄alkyl, and said C₁₋₄alkyl hasone or more hydrogen atoms optionally replaced with deuterium.

R² is selected from H, deuterium or C₁₋₄alkyl, and said C₁₋₄alkyl hasone or more hydrogen atoms optionally replaced with deuterium; and

R³ is C₀₋₄alkyl-CN.

In an embodiment of Formula (II), R² is H.

In another embodiment, R² is deuterium.

In an embodiment of Formula (II), R¹ is methyl.

In an embodiment of Formula (II), R¹ is methyl, with one or morehydrogen atoms attached to the methyl replaced with deuterium.

In an embodiment, R³ is —CN.

In another embodiment, there is provided a compound of Formula (III):

or a pharmaceutically acceptable salt, or deuterated analog thereof,wherein:

R¹ is H, deuterium or methyl, said methyl having one or more hydrogenatoms optionally replaced with deuterium.

In an embodiment, there is provided a compound having the structure:

or a pharmaceutically acceptable salt thereof.

In an embodiment, there is provided a pharmaceutical compositioncomprising a compound herein, or a pharmaceutically acceptable saltthereof, together with a pharmaceutically acceptable carrier.

Another embodiment of the present disclosure provides a pharmaceuticalcomposition comprising a compound of the disclosure, together with apharmaceutically acceptable carrier, and optionally a diluent.

Another embodiment of the present disclosure provides a method oftreating an inflammation related disease or disorder in a patient inneed thereof, comprising administering to said patient a compound of thedisclosure, or a pharmaceutical composition thereof.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The following description sets forth exemplary methods, parameters andthe like. It should be recognized, however, that such description is notintended as a limitation on the scope of the present disclosure but isinstead provided as a description of exemplary embodiments.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —C(O)NH₂is attached through the carbon atom. A dash at the front or end of achemical group is a matter of convenience; chemical groups may bedepicted with or without one or more dashes without losing theirordinary meaning. A wavy line drawn through a line in a structureindicates a point of attachment of a group. Unless chemically orstructurally required, no directionality is indicated or implied by theorder in which a chemical group is written or named.

The prefix “C_(u-v)” indicates that the following group has from u to vcarbon atoms. For example, “C₁₋₆ alkyl” indicates that the alkyl grouphas from 1 to 6 carbon atoms. C₀ indicates that no carbons are present,or in other words, a bond to the next substituent.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. In certain embodiments, the term “about” includes the indicatedamount ±10%. In other embodiments, the term “about” includes theindicated amount ±5%. In certain other embodiments, the term “about”includes the indicated amount ±1%. Also, to the term “about X” includesdescription of “X”. Also, the singular forms “a” and “the” includeplural references unless the context clearly dictates otherwise. Thus,e.g., reference to “the compound” includes a plurality of such compoundsand reference to “the assay” includes reference to one or more assaysand equivalents thereof known to those skilled in the art.

“Alkyl” refers to an unbranched or branched saturated hydrocarbon chain.As used herein, alkyl has 1 to 20 carbon atoms (i.e., C₁₋₂₀ alkyl), 1 to8 carbon atoms (i.e., C₁₋₈ alkyl), 1 to 6 carbon atoms (i.e., C₁₋₆alkyl), or 1 to 4 carbon atoms (i.e., C₁₋₄ alkyl). Examples of alkylgroups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl,2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having aspecific number of carbons is named by chemical name or identified bymolecular formula, all positional isomers having that number of carbonsmay be encompassed; thus, for example, “butyl” includes n-butyl (i.e.,—(CH₂)₃CH₃), sec-butyl (i.e., —CH(CH₃)CH₂CH₃), isobutyl (i.e.,—CH₂CH(CH₃)₂) and tert-butyl (i.e., —C(CH₃)₃); and “propyl” includesn-propyl (i.e., —(CH₂)₂CH₃) and isopropyl (i.e., —CH(CH₃)₂).

“Cyano” refers to the group —CN.

“Halo” refers to —F, —Cl, —Br, —I.

Certain commonly used alternative chemical names may be used. Forexample, a divalent group such as a divalent “alkyl” group, a divalent“aryl” group, etc., may also be referred to as an “alkylene” group or an“alkylenyl” group, an “arylene” group or an “arylenyl” group,respectively. Also, unless indicated explicitly otherwise, wherecombinations of groups are referred to herein as one moiety, e.g.,arylalkyl, the last mentioned group contains the atom by which themoiety is attached to the rest of the molecule.

The terms “optional” or “optionally” means that the subsequentlydescribed event or circumstance may or may not occur, and that thedescription includes instances where said event or circumstance occursand instances in which it does not. Also, the term “optionallysubstituted” refers to any one or more hydrogen atoms on the designatedatom or group may or may not be replaced by a moiety other thanhydrogen. “Optionally substituted” may be zero to the maximum number ofpossible substitutions, and each occurrence is independent. When theterm “substituted” is used, then that substitution is required to bemade at a substitutable hydrogen atom of the indicated substituent. Anoptional substitution may be the same or different from a (required)substitution.

When a moiety is “optionally substituted,” and reference is made to ageneral term, such as any “alkyl,” “alkenyl,” “alkynyl,” “haloalkyl,”“cycloalkyl,” “aryl” or “heteroaryl,” then the general term can refer toany antecedent specifically recited term, such as (C₁₋₃ alkyl), (C₄₋₆alkyl), —O(C₁₋₄ alkyl), (C₃₋₁₀ cycloalkyl), O—(C₃₋₁₀ cycloalkyl) and thelike. For example, “any aryl” includes both “aryl” and as well asexamples of aryl, such as phenyl or naphthyl and the like. Also, theterm “any heterocyclyl” includes heterocyclyls, such as oxetanyl,tetrahydropyranyl, morpholino, piperidinyl and the like. In the samemanner, the term “any heteroaryl” includes heteroaryls, such aspyridine, pyridazine, thiazole, thiadiazole, quinoline and the like.

Some of the compounds exist as tautomers. Tautomers are in equilibriumwith one another. For example, amide containing compounds may exist inequilibrium with imidic acid tautomers. Regardless of which tautomer isshown, and regardless of the nature of the equilibrium among tautomers,the compounds are understood by one of ordinary skill in the art tocomprise both amide and imidic acid tautomers. Thus, the amidecontaining compounds are understood to include their imidic acidtautomers. Likewise, the imidic acid containing compounds are understoodto include their amide tautomers.

Any formula or structure given herein, is also intended to representunlabeled forms as well as isotopically labeled forms of the compounds.Isotopically labeled compounds have structures depicted by the formulasgiven herein except that one or more atoms are replaced by an atomhaving a selected atomic mass or mass number. Examples of isotopes thatcan be incorporated into compounds of the disclosure include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as, but not limited to ²H (deuterium, D), ³H (tritium), ¹¹C, ¹³C,¹⁴C, ¹⁵N, ¹⁸F, ¹⁵O, ¹⁸O, ³¹P, ³²P, ³⁵S, ³⁶Cl and ¹²⁵I. Variousisotopically labeled compounds of the present disclosure, for examplethose into which radioactive isotopes such as ³H, ¹³C and ¹⁴C areincorporated. Such isotopically labelled compounds may be useful inmetabolic studies, reaction kinetic studies, detection or imagingtechniques, such as positron emission tomography (PET) or single-photonemission computed tomography (SPECT) including drug or substrate tissuedistribution assays or in radioactive treatment of patients.

The disclosure also includes “deuterated analogues” of compounds ofFormula I in which from 1 to n hydrogens attached to a carbon atomis/are replaced by deuterium, in which n is the number of hydrogens inthe molecule. Such compounds exhibit increased resistance to metabolismand are thus useful for increasing the half-life of any compound ofFormula I when administered to a mammal, particularly a human. See, forexample, Foster, “Deuterium Isotope Effects in Studies of DrugMetabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compoundsare synthesized by means well known in the art, for example by employingstarting materials in which one or more hydrogens have been replaced bydeuterium.

Deuterium labelled or substituted therapeutic compounds of thedisclosure may have improved DMPK (drug metabolism and pharmacokinetics)properties, relating to distribution, metabolism and excretion (ADME).Substitution with heavier isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life, reduced dosage requirements and/oran improvement in therapeutic index. An ¹⁸F labeled compound may beuseful for PET or SPECT studies. Isotopically labeled compounds of thisdisclosure and prodrugs thereof can generally be prepared by carryingout the procedures disclosed in the schemes or in the examples andpreparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent. Itis understood that deuterium in this context is regarded as asubstituent in the compound of Formula I.

The concentration of such a heavier isotope, specifically deuterium, maybe defined by an isotopic enrichment factor. In the compounds of thisdisclosure any atom not specifically designated as a particular isotopeis meant to represent any stable isotope of that atom. Unless otherwisestated, when a position is designated specifically as “H” or “hydrogen”,the position is understood to have hydrogen at its natural abundanceisotopic composition. Accordingly, in the compounds of this disclosureany atom specifically designated as a deuterium (D) is meant torepresent deuterium.

In many cases, the compounds of this disclosure are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

Provided are also pharmaceutically acceptable salts, hydrates, solvates,tautomeric forms, polymorphs, and prodrugs of the compounds describedherein. “Pharmaceutically acceptable” or “physiologically acceptable”refer to compounds, salts, compositions, dosage forms and othermaterials which are useful in preparing a pharmaceutical compositionthat is suitable for veterinary or human pharmaceutical use.

The term “pharmaceutically acceptable salt” of a given compound refersto salts that retain the biological effectiveness and properties of thegiven compound, and which are not biologically or otherwise undesirable.“Pharmaceutically acceptable salts” or “physiologically acceptablesalts” include, for example, salts with inorganic acids and salts withan organic acid. In addition, if the compounds described herein areobtained as an acid addition salt, the free base can be obtained bybasifying a solution of the acid salt. Conversely, if the product is afree base, an addition salt, particularly a pharmaceutically acceptableaddition salt, may be produced by dissolving the free base in a suitableorganic solvent and treating the solution with an acid, in accordancewith conventional procedures for preparing acid addition salts from basecompounds. Those skilled in the art will recognize various syntheticmethodologies that may be used to prepare nontoxic pharmaceuticallyacceptable addition salts. Pharmaceutically acceptable acid additionsalts may be prepared from inorganic and organic acids. Salts derivedfrom inorganic acids include hydrochloric acid, hydrobromic acid,sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derivedfrom organic acids include acetic acid, propionic acid, glycolic acid,pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid,maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid,cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluene-sulfonic acid, salicylic acid, and the like. Likewise,pharmaceutically acceptable base addition salts can be prepared frominorganic and organic bases. Salts derived from inorganic bases include,by way of example only, sodium, potassium, lithium, ammonium, calciumand magnesium salts. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary and tertiary amines, such asalkyl amines (i.e., NH₂(alkyl)), dialkyl amines (i.e., HN(alkyl)₂),trialkyl amines (i.e., N(alkyl)₃), substituted alkyl amines (i.e.,NH₂(substituted alkyl)), di(substituted alkyl) amines (i.e.,HN(substituted alkyl)₂), tri(substituted alkyl) amines (i.e.,N(substituted alkyl)₃), alkenyl amines (i.e., NH₂(alkenyl)), dialkenylamines (i.e., HN(alkenyl)₂), trialkenyl amines (i.e., N(alkenyl)₃),substituted alkenyl amines (i.e., NH₂(substituted alkenyl)),di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)₂), tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)₃, mono-, di-or tri-cycloalkyl amines (i.e., NH₂(cycloalkyl), HN(cycloalkyl)₂,N(cycloalkyl)₃), mono-, di- or tri-arylamines (i.e., NH₂(aryl),HN(aryl)₂, N(aryl)₃), or mixed amines, etc. Specific examples ofsuitable amines include, by way of example only, isopropylamine,trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine,morpholine, N-ethylpiperidine, and the like.

The term “substituted” means that any one or more hydrogen atoms on thedesignated atom or group is replaced with one or more substituents otherthan hydrogen, provided that the designated atom's normal valence is notexceeded. The one or more substituents include, but are not limited to,alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl,azido, carbamoyl, carboxyl, carboxyl ester, cyano, guanidino, halo,haloalkyl, haloalkoxy, heteroalkyl, heteroaryl, heterocyclyl, hydroxy,hydrazino, imino, oxo, nitro, alkylsulfinyl, sulfonic acid,alkylsulfonyl, thiocyanate, thiol, thione, or combinations thereof.Polymers or similar indefinite structures arrived at by definingsubstituents with further substituents appended ad infinitum (e.g., asubstituted aryl having a substituted alkyl which is itself substitutedwith a substituted aryl group, which is further substituted by asubstituted heteroalkyl group, etc.) are not intended for inclusionherein. Unless otherwise noted, the maximum number of serialsubstitutions in compounds described herein is three. For example,serial substitutions of substituted aryl groups with two othersubstituted aryl groups are limited to ((substituted aryl)substitutedaryl) substituted aryl. Similarly, the above definitions are notintended to include impermissible substitution patterns (e.g., methylsubstituted with 5 fluorines or heteroaryl groups having two adjacentoxygen ring atoms). Such impermissible substitution patterns are wellknown to the skilled artisan. When used to modify a chemical group, theterm “substituted” may describe other chemical groups defined herein.Unless specified otherwise, where a group is described as optionallysubstituted, any substituents of the group are themselves unsubstituted.For example, in some embodiments, the term “substituted alkyl” refers toan alkyl group having one or more substituents including hydroxyl, halo,alkoxy, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In otherembodiments, the one or more substituents may be further substitutedwith halo, alkyl, haloalkyl, hydroxyl, alkoxy, cycloalkyl, heterocyclyl,aryl, or heteroaryl, each of which is substituted. In other embodiments,the substituents may be further substituted with halo, alkyl, haloalkyl,alkoxy, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, each ofwhich is unsubstituted. One skilled in the art will recognize thatsubstituents and other moieties of the compounds of the generic formulaherein should be selected in order to provide a compound which issufficiently stable to provide a pharmaceutically useful compound whichcan be formulated into an acceptably stable pharmaceutical composition.Compounds which have such stability are contemplated as falling withinthe scope of the present invention. It should be understood by oneskilled in the art that any combination of the definitions andsubstituents described above should not result in an inoperable speciesor compound.

As used herein, “pharmaceutically acceptable carrier” or“pharmaceutically acceptable excipient” includes any and all solvents,dispersion media, coatings, antibacterial and antifungal agents,isotonic and absorption delaying agents and the like. The use of suchmedia and agents for pharmaceutically active substances is well known inthe art. Except insofar as any conventional media or agent isincompatible with the active ingredient, its use in the therapeuticcompositions is contemplated. Supplementary active ingredients can alsobe incorporated into the compositions.

A “solvate” is formed by the interaction of a solvent and a compound.Solvates of salts of the compounds described herein are also provided.Hydrates of the compounds described herein are also provided.

Combinations

Patients being treated by administration of the IRAK4 inhibitors of thedisclosure often exhibit diseases or conditions that benefit fromtreatment with other therapeutic agents. These diseases or conditionscan be of an inflammatory nature or can be related to cancer, metabolicdisorders, gastrointestinal disorders and the like. Thus, one aspect ofthe disclosure is a method of treating an inflammation related diseaseor condition, or a metabolic disorder, gastrointestinal disorder, orcancer and the like comprising administering a compound of the incombination with one or more compounds useful for the treatment of suchdiseases to a subject, particularly a human subject, in need thereof.

In some embodiments, a compound of the present disclosure isco-formulated with the additional one or more active ingredients. Insome embodiments, the other active ingredient is administered atapproximately the same time, in a separate dosage form. In someembodiments, the other active ingredient is administered sequentially,and may be administered at different times in relation to a compound ofthe present disclosure.

Combinations for Inflammatory Diseases and Conditions

For example, a compound of the present disclosure may be combined withone or more 5-Lipoxygenase inhibitors, Acetylcholinesterase inhibitors,Acetyl-CoA carboxylase (ACC) inhibitors, ACTH receptor agonists, Activinreceptor antagonists, Acyltransferase inhibitors, Adrenocorticotrophichormone ligands, AKT1 gene inhibitors, Alkaline phosphatase modulators,Alkaline phosphatase stimulators, Androgen receptor agonists,Apolipoprotein C3 antagonists, ASK1 kinase inhibitors, Bactericidalpermeability protein stimulators, Beta adrenoceptor antagonists,Beta-glucuronidase inhibitors, B-lymphocyte antigen CD20 inhibitors,Bradykinin receptor modulators, BTK kinase inhibitors, Calcineurininhibitors, Calcium channel inhibitors, Cannabinoid CB1 receptormodulators, Cannabinoid CB2 receptor modulators, Cannabinoid receptorantagonists, Cannabinoid receptor modulators, Caspase inhibitors,Cathepsin S inhibitors, CCN protein stimulators, CCR3 chemokineantagonists, CCR5 chemokine antagonists, CCR9 chemokine antagonists, CD3modulators, CD40 ligand inhibitors, CD40 ligand receptor antagonists,CD49b antagonists, CD49d antagonists, CD89 agonists, Cell adhesionmolecule inhibitors, Chemokine CXC ligand inhibitors, CHST15 geneinhibitors, Collagen modulators, CSF-1 agonists, CSF-1 antagonists,CXC10 chemokine ligand inhibitors, CXCR2 chemokine antagonists, CyclicGMP phosphodiesterase inhibitors, Cyclooxygenase 2 inhibitors,Cyclooxygenase inhibitors, Cyclooxygenase stimulators, Cytochrome P4503A4 inhibitors, Cytotoxic T-lymphocyte protein-4 stimulators,Dihydroceramide delta 4 desaturase inhibitors, Dihydroorotatedehydrogenase inhibitors, DNA polymerase inhibitors, DPP-4 inhibitors,EGFR family tyrosine kinase receptor modulators, Eosinophil peroxidaseinhibitors, Eotaxin ligand inhibitors, EP4 prostanoid receptor agonists,Epidermal growth factor agonists, Epidermal growth factor ligands,Estrogen receptor beta agonists, Factor XIII agonists, FGF-10 ligands,FGF2 receptor agonists, Fractalkine ligand inhibitors, Free fatty acidreceptor 2 antagonists, FXR agonists, GATA 3 transcription factorinhibitors, Glucagon-like peptide 1 agonists, Glucagon-like peptide 2agonists, Glucocorticoid agonists, GM-CSF receptor agonists, G-proteincoupled receptor 84 antagonists, Guanylate cyclase receptor agonists,Histamine H2 receptor antagonists, Histone acetyl transferaseinhibitors, Histone deacetylase inhibitors, HLA class II antigenmodulators, Hydrolase inhibitors, HSD17β13 inhibitors, ICAM1 geneinhibitors, ICAM-1 inhibitors, IL1 gene inhibitors, IL-10 agonists, IL10gene stimulators, IL-11 agonists, IL-12 antagonists, IL12 geneinhibitors, IL-13 antagonists, IL-17 antagonists, IL-2 antagonists, IL-2receptor alpha subunit inhibitors, IL-21 antagonists, IL-23 antagonists,IL-6 antagonists, IL6 gene inhibitors, IL-6 receptor modulators, IL-7antagonists, IL-8 antagonists, Immunoglobulin G1 agonists,Immunoglobulin G2 modulators, Inosine monophosphate dehydrogenaseinhibitors, Insulin sensitizers, Integrin alpha-4/beta-1 antagonists,Integrin alpha-4/beta-7 antagonists, Integrin alpha-E antagonists,Integrin antagonists, Integrin beta-7 antagonists, Interferon betaligands, Interleukin 17E ligand inhibitors, Interleukin ligandinhibitors, Interleukin receptor 17A antagonists, Interleukin receptor17B antagonists, Interleukin-1 beta ligands, Interleukin-1 beta ligandmodulators, Interleukin-6 ligand inhibitors, JAK tyrosine kinaseinhibitors, Jak1 tyrosine kinase inhibitors, JAK2 gene inhibitors, Jak3tyrosine kinase inhibitors, Jun N terminal kinase inhibitors, LanC likeprotein 2 modulators, Leukotriene BLT receptor antagonists, Lipoxygenasemodulators, L-Selectin antagonists, MAdCAM inhibitors, Matrixmetalloprotease inhibitors, Matrix metalloprotease modulators,Melanocortin agonists, Membrane copper amine oxidase inhibitors,Metalloprotease-2 inhibitors, Metalloprotease-9 inhibitors, MIP 3 alphaligand inhibitors, Mitochondrial 10 kDa heat shock protein stimulators,Monocyte differentiation antigen CD14 inhibitors, mTOR inhibitors, Mucinstimulators, NAD-dependent deacetylase sirtuin-1 stimulators,Natriuretic peptide receptor C agonists, Neuregulin-4 ligands, Nicotinicacetylcholine receptor agonists, Nicotinic ACh receptor alpha 4 subunitmodulators, Nicotinic ACh receptor alpha 7 subunit stimulators,Nicotinic ACh receptor beta 2 subunit modulators, NK1 receptorantagonists, NKG2 D activating NK receptor antagonists, Nuclear factorkappa B inhibitors, Opioid growth factor receptor agonists, Opioidreceptor antagonists, Opioid receptor delta antagonists, Oxidoreductaseinhibitors, P2X7 purinoceptor agonists, p38 MAP kinase inhibitors, PARPinhibitors, PDE 4 inhibitors, PDGF receptor agonists, Phagocytosisstimulating peptide modulators, Phospho MurNAc pentapeptide transferaseinhibitors, Phospholipase A2 inhibitors, Platelet activating factorreceptor antagonists, Potassium channel inhibitors, PPAR alpha agonists,PPAR delta agonists, PPAR gamma agonists, Protein CYR61 stimulators,Protein fimH inhibitors, Protein kinase C alpha inhibitors, Proteinkinase C beta inhibitors, Protein kinase C delta inhibitors, Proteinkinase C epsilon inhibitors, Protein kinase C eta inhibitors, Proteinkinase C theta inhibitors, Protein kinase G inhibitors, Protein kinaseinhibitors, P-selectin glycoprotein ligand-1 inhibitors, PurH purinebiosynthesis protein inhibitors, Retinoic acid receptor alpha agonists,Retinoic acid receptor beta agonists, Retinoid receptor agonists, RNApolymerase inhibitors, SMAD-7 inhibitors, Sodium channel inhibitors,Somatostatin receptor agonists, Sphingosine 1 phosphate phosphatase 1stimulators, Sphingosine 1 phosphate phosphatase modulators, Sphingosinekinase 1 inhibitors, Sphingosine kinase 2 inhibitors,Sphingosine-1-phosphate receptor-1 agonists, Sphingosine-1-phosphatereceptor-1 antagonists, Sphingosine-1-phosphate receptor-1 modulators,Sphingosine-1-phosphate receptor-5 modulators, STAT3 gene inhibitors,STAT-3 inhibitors, STAT-4 inhibitors, Stem cell antigen-1 inhibitors,Superoxide dismutase modulators, Superoxide dismutase stimulators, SYKkinase inhibitors, T cell surface glycoprotein CD28 inhibitors, TGF beta1 ligand inhibitors, Thymulin agonists, THR-β agonists, TLR-2antagonists, TLR-4 antagonists, TLR-9 agonists, TNF alpha ligandinhibitors, TNF alpha ligand modulators, TNF antagonists, TPL2 kinaseinhibitors, Trefoil factor modulators, Tryptase inhibitors, Tryptophan5-hydroxylase inhibitors, Tumor necrosis factor 14 ligand modulators,TYK2 kinase inhibitors, Type I TNF receptor antagonists, Type II TNFreceptor modulators, Unspecified growth factor receptor modulators,Vanilloid VR1 agonists, Vitamin D3 receptor agonists, Zonulininhibitors, abatacept; acemannan; adalimumab; DCCT-10; apremilast;AST-120; balsalazide; balsalazide sodium; basiliximab; beclomethasonedipropionate; budesonide; D-9421; budesonide MMX; catridecacog;certolizumab pegol; Clostridium butyricum; etanercept; fingolimod;glatiramer acetate; golimumab; infliximab; infliximab biosimilar;infliximab follow-on biologic; interferon beta-1a; lenalidomide;mesalazine; GED-0001; AJG-501; metenkefalin acetate with tridecactideacetat, mycophenolate mofetil; naltrexone; natalizumab; nitazoxanide;olsalazine; oprelvekin; propionyl-L-camitine; recombinant interferonbeta-1a; remestemcel-L; rifaximin; rituximab; ropivacaine;rosiglitazone; sargramostim; secukinumab; SPD-480; tacrolimus;tamibarotene; teduglutide; thalidomide; tocilizumab; RO-4877533;tofacitinib; CP-690550; Trichuris suis ova; ASP-1002; ustekinumab;valganciclovir; vedolizumab; zileuton; anti-CD3 imaging agent (antibodyfragment, cancer/autoimmune disease), ImaginAb; AVX-470; ciclosporin;CXCR1/2 ligands mAb (immunology), Eli Lilly; FFP-102; GSK-3050002;INN-108; IR-777; SGM-1019; peg-ilodecakin; PF-06480605; PF-06651600;SER-287; Syn-1002; Thetanix; tolerogenic dendritic cell therapyTOP-1288; VBY-036; VBY-129; 946414-98-8; BMS-936557; 99mTc-annexinV-128; ABC-294640; abrilumab; Alequel; AMG-139; amiselimod; APD-334;ASP-3291; beclomethasone dipropionate; bertilimumab; ciclosporin;clazakizumab; DLX-105; dolcanatide; E-6011; ETX-201; FFP-104;filgotinib; foralumab; GED-0507-34-Levo; givinostat; GLPG-0974;GLPG-1205; iberogast N (ulcerative colitis), Bayer; BAY98-7410; INV-103;JNJ-40346527; K(D)PT; KAG-308; KHK-4083; KRP-203; larazotide acetate;CB-01-05-MMX; LY-3074828; mesalamine with N-acetylcysteine; midismase;molgramostim follow on biologic with fosfomycin with carbapenem,Reponex; multipotent adult progenitor cell therapy (ischemia/cerebralpalsy), Athersys/Heabos; NN-8828; olokizumab; OvaSave; P-28-GST;PDA-002; PF-4236921; PF-547659; prednisolone; PUR-0110; QBECO; RBX-2660;repurposed naltrexone; JKB-122; SB-012; sotrastaurin; STNM-01; TAK-114;tetomilast; Debio-0512; TRK-170; TRX-318; vatelizumab; VB-201; ZP-1848;zucapsaicin; ABT-494; alicaforsen; Ampion; BI-655066; briakinumab;cannabidiol; carotegast methyl; cobitolimod; dexamethasone sodiumphosphate; elafibranor; etrolizumab; GS-5745; HMPL-004; LP-02;mesalazine; metronidazole mongersen; ocrelizumab; ozanimod; peficitinib;RHB-104; rifaximin; tildrakizumab; tralokinumab; brodalumab; laquinimod;plecanatide; telotristat etiprate; infliximab biosimilar, SamsungBioepis; AZD-058; and rifabutin with clarithromycin and further withclofazimine.

Also, the following non-exhaustive list of classes of compounds andcompounds may be combined with a compound of the present disclosure:5-Lipoxygenase inhibitors, such as zileuton, etalocibm FPL-64170,E-3040, and BU-4601A; Acetylcholinesterase inhibitors, such as BL-7040;ACTH receptor agonists, such as metenkefalin acetate with tridecactideacetate, and FAR-404; Activin receptor antagonists such as follistatin;Acyltransferase inhibitors such as AZD-0585; Adrenocorticotrophichormone ligands, such as metenkefalin acetate with tridecactide acetate,and FAR-404; AKT1 gene inhibitors, such as vidofludimus; Alkalinephosphatase modulators such as recombinant human alkaline phosphatase(oral, ulcerative colitis), AM-Pharma; Alkaline phosphatase stimulatorssuch as bovine alkaline phosphatase; Androgen receptor agonists, such asPB-005; Apolipoprotein C3 antagonists, such as AZD-0585; Bactericidalpermeability protein stimulators, such as opebacan; Beta adrenoceptorantagonists, such as NM-001; Beta-glucuronidase inhibitors, such asKD-018; B-lymphocyte antigen CD20 inhibitors, such as ocrelizumab,rituximab; Bradykinin receptor modulators, such as givinostat;Calcineurin inhibitors, such as tacrolimus, ciclosporin; Calcium channelinhibitors, such as clotrimazole; Cannabinoid CB1 receptor modulators,such as GWP42003-P, cannabidiol; Cannabinoid CB2 receptor modulators,such as GWP42003-P, cannabidiol; Cannabinoid receptor antagonists, suchas fingolimod; Cannabinoid receptor modulators, such as GWP42003-P,cannabidiol; Cathepsin S inhibitors, such as VBY-129, VBY-036; CCNprotein stimulators, such as CSA-13; CCR3 chemokine antagonists, such asbertilimumab; CCR5 chemokine antagonists, such as HGS-1025; CCR9chemokine antagonists, such as MLN-3126, vercimon, CCX-025; CD3modulators, such as visilizumab; CD40 ligand inhibitors, such asFFP-104; CD40 ligand receptor antagonists, such as FFP-104, FFP-102,toralizumab; CD49b antagonists, such as vatelizumab; CD49d antagonists,such as ELND-004; CD89 agonists, such as HF-1020; Cell adhesion moleculeinhibitors, such as natalizumab, alicaforsen (intravenous), ASP-2002,ISIS-2302; Chemokine CXC ligand inhibitors, such as CXCR1/2 ligands mAh(immunology), Eli Lilly; CHST15 gene inhibitors, such as STNM-01;Collagen modulators, such as adipose-derived stem cell therapy (CelutionSystem), Cytori, DCCT-10; CSF-1 agonists, such as sargramostim,molgramostim follow on biologic with fosfomycin with carbapenem(intraintestinal, Crohn's disease), Reponex; CSF-1 antagonists, such asJNJ-40346527; CXC10 chemokine ligand inhibitors, such as 946414-98-8,BMS-936557; CXCR2 chemokine antagonists, such as elubrixin; Cyclic GMPphosphodiesterase inhibitors, such as CEL-031; Cyclooxygenase 2inhibitors, such as P-54; Cyclooxygenase inhibitors, such as mesalazine,4-aminosalicylate sodium, AJG-501, AGI-022; Cyclooxygenase stimulators,such as nicotine polacrilex; Cytochrome P450 3A4 inhibitors, such asKD-018; Cytotoxic T-lymphocyte protein-4 stimulators, such as abatacept;Dihydroceramide delta 4 desaturase inhibitors, such as ABC-294640;Dihydroorotate dehydrogenase inhibitors, such as vidofludimus; DNApolymerase inhibitors, such as valganciclovir; EGFR family tyrosinekinase receptor modulators, such as neuregulin 4 (Crohn'sdisease/ulcerative colitis/necrotizing enterocolitis), AvexegenTherapeutics/Children's Hospital of Los Angeles; Eosinophil peroxidaseinhibitors, such as AWEPOPD-01, AWEPO-003; Eotaxin ligand inhibitors,such as bertilimumab; EP4 prostanoid receptor agonists, such as KAG-308;Epidermal growth factor agonists, such as heparin-EGF-like factor, SciosNova; Epidermal growth factor ligands, such as Hebervis; Estrogenreceptor beta agonists, such as prinaberel; Factor XIII agonists, suchas catridecacog; FGF-10 ligands, such as repifermin; FGF2 receptoragonists, such as F2A; Fractalkine ligand inhibitors, such as E-6011;Free fatty acid receptor 2 antagonists, such as GLPG-0974; GATA 3transcription factor inhibitors, such as SB-012; Glucagon-like peptide 2agonists, such as teduglutide, ZP-1848, NB-1002; Glucocorticoidagonists, such as budesonide, beclomethasone dipropionate, dexamethasonesodium phosphate, AJG-511, DOR-201, D-9421-C; GM-CSF receptor agonists,such as sargramostim, molgramostim follow on biologic with fosfomycinwith carbapenem (intraintestinal, Crohn's disease), Reponex; G-proteincoupled receptor 84 antagonists, such as GLPG-1205; Guanylate cyclasereceptor agonists, such as dolcanatide, SP-333; Histamine H2 receptorantagonists, such as bismuth, Medeva; Histone acetyltransferaseinhibitors, such as TIP60 inhibitors (ulcerative colitis/inflammatorybowel disease/autoimmune diseases), University of Pennsylvania; Histonedeacetylase inhibitors, such as givinostat; HLA class II antigenmodulators, such as HLA class II protein modulators (Crohns disease),Nextera AS; Hydrolase inhibitors, such as SC-56938; ICAM1 geneinhibitors, such as alicaforsen; ICAM-1 inhibitors, such as alicaforsen(intravenous), ISIS-2302; IL1 gene inhibitors, such as PLR-14; IL-10agonists, such as peg-ilodecakin, AM-0010; IL10 gene stimulators, suchas gene therapy (IL-10), Imperial College; IL-11 agonists, such asoprelvekin, YM-294; IL-12 antagonists, such as ustekinumab, briakinumab,apilimod; IL12 gene inhibitors, such as RDP-58; IL-13 antagonists, suchas tralokinumab, anrukinzumab; IL-17 antagonists, such as secukinumab,vidofludimus; IL-2 antagonists, such as daclizumab; IL-2 receptor alphasubunit inhibitors, such as basiliximab, daclizumab, BSX-003,Ro-34-7375; IL-21 antagonists, such as NN-8828, ATR-107; IL-23antagonists, such as tildrakizumab, ustekinumab, BI-655066, AMG-139,briakinumab, LY-3074828, apilimod; IL-6 antagonists, such astocilizumab, clazakizumab, olokizumab, HMPL-004, AMG-220, FM-101; IL6gene inhibitors, such as YSIL6-T-PS; IL-6 receptor modulators, such astocilizumab; IL-7 antagonists, such as interleukin-7 receptor modulators(ulcerative colitis/T-cell acute lymphoblastic leukaemia), Effimune;IL-8 antagonists, such as elubrixin, clotrimazole; Immunoglobulin G1agonists, such as HF-1020; Immunoglobulin G2 modulators, such asPF-547659; Inosine monophosphate dehydrogenase inhibitors, such asmycophenolate mofetil; Insulin sensitizers, such as elafibranor,rosiglitazone, HE-3286, EGS-21; Integrin alpha-4/beta-1 antagonists,such as natalizumab, TRK-170, firategrast; Integrin alpha-4/beta-7antagonists, such as etrolizumab, vedolizumab, abrilumab, carotegastmethyl, TRK-170, firategrast; Integrin alpha-E antagonists, such asetrolizumab; Integrin antagonists, such as vatelizumab, ASP-2002;Integrin beta-7 antagonists, such as etrolizumab; Interferon betaligands, such as interferon beta-1a, recombinant interferon beta-1a,Serono; Interleukin 17E ligand inhibitors, such as anti-IL-17BRhumanized antibody (lung fibrosis/asthma/ulcerative colitis), MedicalResearch Council Technology; Interleukin ligand inhibitors, such asHE-3286; Interleukin receptor 17A antagonists, such as brodalumab;Interleukin receptor 17B antagonists, such as anti-IL-17BR humanizedantibody (lung fibrosis/asthma/ulcerative colitis), Medical ResearchCouncil Technology; Interleukin-1 beta ligands, such as K(D)PT,PUR-0110, HMPL-004; Interleukin-1 beta ligand modulators, such asPUR-0110, HMPL-004; Interleukin-6 ligand inhibitors, such as PF-4236921;JAK tyrosine kinase inhibitors, such as tofacitinib, peficitinib; Jak1tyrosine kinase inhibitors, such as ABT-494, tofacitinib, filgotinib,peficitinib, GLPG-0555, solcitinib; JAK2 gene inhibitors, such asvidofludimus; Jak3 tyrosine kinase inhibitors, such as tofacitinib,peficitinib; Jun N terminal kinase inhibitors, such as semapimod; LanClike protein 2 modulators, such as BT-11; Leukotriene BLT receptorantagonists, such as ONO-4057, etalocib, SC-53228, SC-52798;Lipoxygenase modulators, such as mesalazine; L-Selectin antagonists,such as BNP-001; MAdCAM inhibitors, such as vedolizumab, PF-547659;Matrix metalloprotease inhibitors, such as D-5410; Matrixmetalloprotease modulators, such as D-5410; Melanocortin agonists, suchas ASP-3291; Membrane copper amine oxidase inhibitors, such asvepalimomab; Metalloprotease-2 inhibitors, such as KD-018, RWJ-68354;Metalloprotease-9 inhibitors, such as GS-5745; MIP 3 alpha ligandinhibitors, such as GSK-3050002; Mitochondrial 10 kDa heat shock proteinstimulators, such as INV-103; Monocyte differentiation antigen CD14inhibitors, such as CD14 anti-inflammatory, Cornell; mTOR inhibitors,such as P-2281; Mucin stimulators, such as rebamipide; NAD-dependentdeacetylase sirtuin-1 stimulators, such as SRT-2104; Natriuretic peptidereceptor C agonists, such as plecanatide; Neuregulin-4 ligands, such asneuregulin 4 (Crohn's disease/ulcerative colitis/necrotizingenterocolitis), Avexegen Therapeutics/Children's Hospital of LosAngeles; Nicotinic acetylcholine receptor agonists, such as TC-2403,nicotine polacrilex, nicotine; Nicotinic ACh receptor alpha 4 subunitmodulators, such as TC-2403; Nicotinic ACh receptor alpha 7 subunitstimulators, such as GTS-21; Nicotinic ACh receptor beta 2 subunitmodulators, such as TC-2403; NK1 receptor antagonists, such as KD-018,nolpitantium besilate; NKG2 D activating NK receptor antagonists, suchas NNC-0142-002; Nuclear factor kappa B inhibitors, such as KD-018,cobitolimod, CSA-13, HE-3286, HMPL-004, Avrina, mesalamine withN-acetylcysteine, P-54; Opioid growth factor receptor agonists, such asmetenkefalin acetate with tridecactide acetate, FAR-404; Opioid receptorantagonists, such as naltrexone, IRT-103; Opioid receptor deltaantagonists, such as KD-018; Oxidoreductase inhibitors, such asolsalazine; P2X7 purinoceptor agonists, such as givinostat; p38 MAPkinase inhibitors, such as RDP-58, doramapimod, semapimod, RWJ-68354;PARP inhibitors, such as EB-47, INO-1003; PDE 4 inhibitors, such asapremilast, tetomilast, CC-1088; PDGF receptor agonists, such asoprelvekin, YM-294; Phagocytosis stimulating peptide modulators, such as99mTc-RP-128; Phospho MurNAc pentapeptide transferase inhibitors, suchas SQ-641; Phospholipase A2 inhibitors, such as varespladib methyl;Platelet activating factor receptor antagonists, such as dersalazinesodium; Potassium channel inhibitors, such as clotrimazole; PPAR alphaagonists, such as elafibranor (GFT-1007); PPAR delta agonists, such aselafibranor (GFT-1007); PPAR gamma agonists, such as rosiglitazone,GED-0507-34-Levo, etalocib; Protein CYR61 stimulators, such as CSA-13;Protein fimH inhibitors, such as EB-8018; Protein kinase C alphainhibitors, such as sotrastaurin (AEB-071); Protein kinase C betainhibitors, such as sotrastaurin (AEB-071); Protein kinase C deltainhibitors, such as sotrastaurin (AEB-071); Protein kinase C epsiloninhibitors, such as sotrastaurin (AEB-071); Protein kinase C etainhibitors, such as sotrastaurin (AEB-071); Protein kinase C thetainhibitors, such as sotrastaurin (AEB-071); Protein kinase G inhibitors,such as CEL-031; Protein kinase inhibitors, such as TOP-1288; P-selectinglycoprotein ligand-1 inhibitors, such as SEL-K2; PurH purinebiosynthesis protein inhibitors, such as mycophenolate mofetil; Retinoicacid receptor alpha agonists, such as tamibarotene; Retinoic acidreceptor beta agonists, such as tamibarotene; Retinoid receptoragonists, such as tamibarotene; RNA polymerase inhibitors, such asrifaximin; SMAD-7 inhibitors, such as mongersen (GED-0301); Sodiumchannel inhibitors, such as ropivacaine; Somatostatin receptor agonists,such as vapreotide; Sphingosine 1 phosphate phosphatase 1 stimulators,such as APD-334; Sphingosine 1 phosphate phosphatase modulators, such asSIP modulators (oral, multiple sclerosis/ulcerative colitis/rheumatoidarthritis), Akaal Pharma; Sphingosine kinase 1 inhibitors, such asABC-294640; Sphingosine kinase 2 inhibitors, such as ABC-294640;Sphingosine-1-phosphate receptor-1 agonists, such as ozanimod(RPC-1063), KRP-203; Sphingosine-1-phosphate receptor-1 antagonists,such as amiselimod (MT-1303); Sphingosine-1-phosphate receptor-1modulators, such as fingolimod (FTY-720), ozanimod (RPC-1063),amiselimod (MT-1303); Sphingosine-1-phosphate receptor-5 modulators,such as ozanimod; STAT3 gene inhibitors, such as vidofludimus; STAT-3inhibitors, such as TAK-114; STAT-4 inhibitors, such as STAT-4 antisenseoligonucleotide (Crohns disease/colitis), NIAID; Stem cell antigen-1inhibitors, such as Ampion, DMI-9523; Superoxide dismutase modulators,such as midismase, LT-0011; Superoxide dismutase stimulators, such assuperoxide dismutase; T cell surface glycoprotein CD28 inhibitors, suchas abatacept; TGF beta 1 ligand inhibitors, such as mongersen, GED-0301;Thymulin agonists, such as Syn-1002; TLR-2 antagonists, such as VB-201;TLR-4 antagonists, such as JKB-122, VB-201; TLR-9 agonists, such asBL-7040, cobitolimod; TNF alpha ligand inhibitors, such as adalimumab,certolizumab pegol, infliximab biosimilar, infliximab, golimumab,ISIS-104838, CSA-13, DLX-105, adalimumab biosimilar, dersalazine sodium,Debio-0512, HMPL-004, DLX-105, infliximab follow-on biologic, AZD-9773,CYT-020-TNFQb, DOM-0200; TNF alpha ligand modulators, such as PUR-0110,CDP-571; TNF antagonists, such as etanercept, certolizumab pegol,AVX-470, onercept; Trefoil factor modulators, such as AG-012; Tryptaseinhibitors, such as APC-2059; Tryptophan 5-hydroxylase inhibitors, suchas telotristat etiprate; Tumor necrosis factor 14 ligand modulators,such as SAR-252067; Type I TNF receptor antagonists, such as DOM-0100;Type II TNF receptor modulators, such as etanercept; Unspecified growthfactor receptor modulators, such as AP-005; Vanilloid VR1 agonists, suchas zucapsaicin; Vitamin D3 receptor agonists, such as calcitriol; andZonulin inhibitors, such as larazotide acetate, AT-1001.

Also, the following non-exhaustive list of classes of compounds andcompounds may be combined with a compound of the present disclosure:14-3-3 protein eta inhibitors, 5-Lipoxygenase inhibitors, Abl tyrosinekinase inhibitors, ACTH receptor agonists, Adenosine A3 receptoragonists, Adenosine deaminase inhibitors, ADP ribosyl cyclase-1modulators, ADP ribosylation factor 6 inhibitors, Adrenocorticotrophichormone ligands, Aggrecanase-2 inhibitors, Albumin modulators, APItranscription factor inhibitors, Basigin inhibitors, Bcr proteininhibitors, B-lymphocyte antigen CD19 inhibitors, B-lymphocyte antigenCD20 inhibitors, B-lymphocyte antigen CD20 modulators, B-lymphocytestimulator ligand inhibitors, Bradykinin receptor modulators, BRAF geneinhibitors, Branched amino acid aminotransferase 1 inhibitors,Bromodomain containing protein inhibitors, Btk tyrosine kinaseinhibitors, Cadherin-11 antagonists, Calcineurin inhibitors, Calciumchannel inhibitors, Carbonic anhydrase inhibitors, Cathepsin Kinhibitors, Cathepsin S inhibitors, CCR1 chemokine antagonists, CCR2chemokine antagonists, CCR3 gene modulators, CCR5 chemokine antagonists,CD126 antagonists, CD29 modulators, CD3 modulators, CD39 agonists, CD4agonists, CD4 antagonists, CD40 ligand inhibitors, CD40 ligand receptorantagonists, CD40 ligand receptor modulators, CD52 antagonists, CD73agonists, CD79b modulators, CD80 antagonists, CD86 antagonists, CD95antagonists, Cell adhesion molecule inhibitors, Choline kinaseinhibitors, Clusterin stimulators, Complement C5 factor inhibitors,Complement Factor stimulators, C-reactive protein inhibitors, CSF-1antagonists, CXC10 chemokine ligand inhibitors, CXCR4 chemokineantagonists, Cyclin-dependent kinase inhibitor 1 inhibitors,Cyclin-dependent kinase-2 inhibitors, Cyclin-dependent kinase-4inhibitors, Cyclin-dependent kinase-5 inhibitors, Cyclin-dependentkinase-6 inhibitors, Cyclin-dependent kinase-7 inhibitors,Cyclin-dependent kinase-9 inhibitors, Cyclooxygenase 2 inhibitors,Cyclooxygenase 2 modulators, Cyclooxygenase inhibitors, Cytosolicphospholipase A2 inhibitors, Cytotoxic T-lymphocyte protein-4modulators, Cytotoxic T-lymphocyte protein-4 stimulators, DHFRinhibitors, Diamine acetyltransferase inhibitors, Dihydroorotatedehydrogenase inhibitors, Elongation factor 2 inhibitors, Eotaxin 2ligand inhibitors, EP4 prostanoid receptor antagonists, Erythropoietinreceptor agonists, Fas ligands, FGF-2 ligand inhibitors, FK506 bindingprotein-12 modulators, Folate antagonists, Folate receptor agonists,Folate receptor beta antagonists, Folate receptor modulators,Fractalkine ligand inhibitors, Fyn tyrosine kinase inhibitors, G proteincoupled receptor 15 antagonists, GABA A receptor modulators,Glucocorticoid agonists, Glucocorticoid antagonists, Glucocorticoidinduced leucine zipper stimulators, GM-CSF ligand inhibitors, GM-CSFreceptor antagonists, GM-CSF receptor modulators, Growth regulatedprotein alpha ligand inhibitors, Hwith Kwith ATPase inhibitors,Histamine H4 receptor antagonists, Histone deacetylase inhibitors,Histone deacetylase-6 inhibitors, HIV-1 gp120 protein inhibitors, HLAclass II antigen DQ-2 alpha modulators, HLA class II antigen inhibitors,HLA class II antigen modulators, Hsp 70 family inhibitors, Hypoxiainducible factor-1 inhibitors, IFNB gene stimulators, I-kappa B kinasebeta inhibitors, I-kappa B kinase inhibitors, IL-1 antagonists, IL-10agonists, IL-11 agonists, IL-12 antagonists, IL-15 antagonists, IL-17antagonists, IL-17 receptor modulators, IL-2 agonists, IL-2 antagonists,IL-21 antagonists, IL-23 antagonists, IL-3 antagonists, IL-4 agonists,IL-6 antagonists, IL-6 receptor modulators, Immunoglobulin antagonists,Immunoglobulin G1 agonists, Immunoglobulin G1 antagonists,Immunoglobulin G1 modulators, Immunoglobulin G2 antagonists,Immunoglobulin G2 modulators, Immunoglobulin gamma Fc receptor IImodulators, Immunoglobulin gamma Fc receptor IIB antagonists,Immunoglobulin kappa modulators, Immunoglobulin M antagonists, Induciblenitric oxide synthase inhibitors, Inosine monophosphate dehydrogenaseinhibitors, Insulin sensitizers, Integrin alpha-1/beta-1 antagonists,Integrin alpha-4/beta-1 antagonists, Integrin antagonists, Interferonbeta ligands, Interferon gamma ligands, Interleukin 17A ligandinhibitors, Interleukin 17F ligand inhibitors, Interleukin 23Ainhibitors, Interleukin ligands, Interleukin receptor 17A antagonists,Interleukin-1 beta ligand inhibitors, Interleukin-10 ligands,Interleukin-2 ligands, Interleukin-4 ligands, Interleukin-6 ligandinhibitors, Itk tyrosine kinase inhibitors, JAK tyrosine kinaseinhibitors, Jak1 tyrosine kinase inhibitors, Jak2 tyrosine kinaseinhibitors, JAK3 gene inhibitors, Jak3 tyrosine kinase inhibitors, Jun Nterminal kinase inhibitors, KCNA voltage-gated potassium channel-3modulators, Kelch like ECH associated protein 1 modulators, Kit tyrosinekinase inhibitors, LanC like protein 2 modulators, LITAF geneinhibitors, Lymphocyte function antigen-3 receptor antagonists, Lyntyrosine kinase inhibitors, Macrophage mannose receptor 1 modulators,MAdCAM inhibitors, MAP kinase modulators, MAP3K2 gene inhibitors,MAPKAPK5 inhibitors, Matrix metalloprotease inhibitors, MCL1 geneinhibitors, MEK protein kinase inhibitors, MEK-1 protein kinaseinhibitors, MEK-2 protein kinase inhibitors, Membrane copper amineoxidase inhibitors, Metalloprotease-2 inhibitors, Metalloprotease-9inhibitors, Midkine ligand inhibitors, Mitochondrial 10 kDa heat shockprotein stimulators, mTOR complex 1 inhibitors, mTOR inhibitors, NAD ADPribosyltransferase stimulators, NAMPT gene inhibitors, NF kappa Binhibitor stimulators, NFAT gene inhibitors, NFE2L2 gene stimulators,Nicotinic acetylcholine receptor antagonists, NK cell receptormodulators, NKG2 A B activating NK receptor antagonists, NKG2 Dactivating NK receptor antagonists, Nuclear erythroid 2-related factor 2stimulators, Nuclear factor kappa B inhibitors, Nuclear factor kappa Bmodulators, Nuclear factor kappa B p105 inhibitors, Opioid growth factorreceptor agonists, Opioid receptor delta antagonists, Osteoclastdifferentiation factor antagonists, Osteoclast differentiation factorligand inhibitors, Oxidoreductase inhibitors, P2X7 purinoceptoragonists, p38 MAP kinase alpha inhibitors, p38 MAP kinase inhibitors,PDE 4 inhibitors, PDE 5 inhibitors, PDGF receptor agonists, PDGFreceptor antagonists, PDGF-B ligand inhibitors, PERK gene inhibitors,Phosphoinositide-3 kinase delta inhibitors, Phosphoinositide-3 kinasegamma inhibitors, Phospholipase A2 inhibitors, Platelet activatingfactor receptor antagonists, PPAR gamma agonists, Programmed cell deathprotein 1 modulators, Prostaglandin D synthase stimulators, Proteinarginine deiminase inhibitors, Protein tyrosine kinase inhibitors, PurHpurine biosynthesis protein inhibitors, Rho associated protein kinase 2inhibitors, Seprase inhibitors, Signal transducer CD24 modulators,Signal transduction inhibitors, Sodium glucose transporter-2 inhibitors,Sphingosine 1 phosphate phosphatase modulators, STAT3 gene inhibitors,Superoxide dismutase stimulators, SYK family tyrosine kinase inhibitors,Syk tyrosine kinase inhibitors, Syndecan-1 inhibitors, T cell receptorantagonists, T cell receptor modulators, T cell surface glycoproteinCD28 inhibitors, T cell surface glycoprotein CD28 stimulators, TAK1binding protein modulators, Talin modulators, T-cell differentiationantigen CD6 inhibitors, T-cell surface glycoprotein CD8 inhibitors,Tenascin modulators, TGF beta agonists, Thymulin agonists, TLR-2antagonists, TLR-4 antagonists, TLR-9 antagonists, TNF alpha ligandinhibitors, TNF alpha ligand modulators, TNF antagonists, TNF geneinhibitors, TNF receptor modulators, TNFSF11 gene inhibitors,Transcription factor p65 inhibitors, Transcription factor RelBinhibitors, Transferrin modulators, Tumor necrosis factor 13C receptorantagonists, Tumor necrosis factor 15 ligand inhibitors, Tumor necrosisfactor ligand 13 inhibitors, Tumor necrosis factor ligand inhibitors,Type I IL-1 receptor antagonists, Type I TNF receptor antagonists, TypeII TNF receptor modulators, Unspecified GPCR agonists, VEGF receptorantagonists, VEGF-2 receptor antagonists, VEGF-2 receptor modulators,VEGF-B ligand inhibitors, X-linked inhibitor of apoptosis proteininhibitors, Zap70 tyrosine kinase inhibitors, 99mTc labelled annexinV-128, abatacept, abatacept biosimilar, ABBV-257, ABT-122, ABT-494,acalabrutinib, aceclofenac, actarit, MS-392, adalimumab, adalimumabbiosimilar, adalimumab follow-on biologic, AK-106, ALX-0061,aminopterin, anakinra, anakinra biosimilar, anakinra follow-on biologic,ARG-301, ASLAN-003, ASP-5094, AT-132, AZD-9567, baricitinib, BI-655064,bimekizumab, BiP (rheumatoid arthritis), Kings College London, BLHP-006,blisibimod, BMS-986104, BMS-986142, ABBV-105, BTT-1023, canakinumab,Cartistem, CCX-354, CD24-IgFc, celecoxib, cerdulatinib, certolizumabpegol, CF-101, CFZ-533, CHR-5154, cibinetide, ciclosporin, clazakizumab,CNTO-6785, corticotropin, Mallinckrodt, CR-6086, CreaVax-RA, CWG-92,CWG-940, Cx-611, DE-098, deflazacort, Rheumavax, denosumab, diacerein,diclofenac, E-6011, eicosapentaenoic acid monoglycerides, etanercept,etanercept biosimilar, etanercept follow-on biologic, etodolac,etoricoxib, filgotinib, fosdagrocorat, gerilimzumab, ginsenoside C-K,givinostat, goat polyclonal antibodies, golimumab, GS-5745, GS-9876,GSK-3196165, HM-71224, HMPL-523, hyaluronate sodium, IB-RA (injectable,rheumatoid arthritis), Innobioscience, IB-RA (oral, rheumatoidarthritis), Innobioscience, iguratimod, IMD-2560, imidazole salicylate,infliximab, infliximab biobetter, infliximab biosimilar, INSIX RA,interferon gamma follow-on biologic, interleukin-2 (injectable),interleukin-2 follow-on biologic, INV-103, IR-501, itolizumab,JNJ-40346527, Ka Shu Ning, KD-025, ketoprofen with omeprazole,leflunomide, lenzilumab, LLDT-8, lumiracoxib, LY-3090106, masitinib,mavrilimumab, MBS-2320, MEDI-5117, meloxicam, methotrexate, MGD-010,misoprostol with diclofenac, MM-A01-01, monalizumab, MORAb-022,MPC-300-IV, MRC-375, nabumetone, namilumab, naproxen with esomeprazole,naproxen with esomeprazole strontium, ocaratuzumab, ofatumumab, OHR-118,olokizumab, OM-89, once-daily naproxen (oral controlled release, pain),Alvogen, ONO-4059, Oralgam, ozoralizumab, peficitinib, pelubiprofen,PF-06687234, piperidone hydrochloridum, piroxicam, prednisolone,prednisone, Prosorba, PRT-2607, PRTX-100, PRX-167700, QBSAU, rabeximod,RCT-18, recombinant human CD22 monoclonal antibody (iv infusion), LonnRyonn Pharma/SinoMab Bioscience (Shenzhen), recombinant humaninterleukin-1 receptor antagonist (rheumatoid arthritis), ShanghaiFudan-Zhangjiang Bio-Pharmaceutical, recombinant human interleukin-2recombinant TNF receptor 2-Fc fusion protein mutant, RG-6125, RhuDex,rifabutin with clarithromycin with clofazimine, rituximab, rituximabbiosimilar, rituximab follow-on biologic, RPI-78, SAN-300, sarilumab,SBI-087, seliciclib, SHR-0302, sirukumab, spebrutinib, SSS-07,KDDF-201110-06, Syn-1002, T-5224, TAB-08, tacrolimus, TAK-020, TAK-079,tarenflurbil (transdermal spraygel, skin disease/rheumatoid arthritis),MIKA Pharma/GALENpharma, technetium Tc 99m tilmanocept,technetium[99Tc]methylenediphosphonate, tenoxicam, Debio-0512,tocilizumab, tofacitinib, Trichuris suis ova, umbilical cord-derivedmesenchymal stem cells (iv, RA/liver disease), Alliancells/ZhongyuanUnion, ustekinumab, VAY-736, VB-201, WF-10, XmAb-5871, YHB-1411-2;14-3-3 protein eta inhibitors, such as anti-AGX-020 mAbs (rheumatoidarthritis), Augurex; 5-Lipoxygenase inhibitors, such as tenoxicam,darbufelone, tebufelone, licofelone, ZD-2138, etalocib, tenidap,tepoxalin, flobufen, SKF-86002, PGV-20229, L-708780, WY-28342, T-0757,T-0799, ZM-216800, L-699333, BU-4601A, SKF-104351, CI-986; Abl tyrosinekinase inhibitors, such as imatinib; ACTH receptor agonists, such asFAR-404, metenkefalin acetate with tridecactide acetate; Adenosine A3receptor agonists, such as CF-101; Adenosine deaminase inhibitors, suchas cladribine, pentostatin, FR-221647; ADP ribosyl cyclase-1 modulators,such as indatuximab ravtansine; ADP ribosylation factor 6 inhibitors,such as NAV-2729; Adrenocorticotrophic hormone ligands, such ascorticotropin, Mallinckrodt, FAR-404, metenkefalin acetate withtridecactide acetate; Aggrecanase-2 inhibitors, such as GIBH-R-001-2;Albumin modulators, such as ALX-0061, ONS-1210; API transcription factorinhibitors, such as T-5224, tarenflurbil, SP-10030; Basigin inhibitors,such as ERG-240; Bcr protein inhibitors, such as imatinib; B-lymphocyteantigen CD19 inhibitors, such as XmAb-5871, MDX-1342; B-lymphocyteantigen CD20 inhibitors, such as ocrelizumab, ofatumumab, rituximab,rituximab biosimilar, veltuzumab, rituximab follow-on biologic,ocaratuzumab, BLX-301, IDEC-102, ABP-798, GP-2013, MK-8808, HLX-01,CT-P10, TL-011, PF-05280586, IBPM-001RX, IBI-301, AME-133v, BCD-020,BT-D004, SAIT-101; B-lymphocyte antigen CD20 modulators, such asrituximab biosimilar, SBI-087, TRU-015, DXL-625; B-lymphocyte stimulatorligand inhibitors, such as belimumab, RCT-18, blisibimod, tabalumab,atacicept, briobacept; Bradykinin receptor modulators, such asgivinostat; BRAF gene inhibitors, such as binimetinib; Branched aminoacid aminotransferase 1 inhibitors, such as ERG-240; Bromodomaincontaining protein inhibitors, such as RVX-297, ZEN-003694; Btk tyrosinekinase inhibitors, such as acalabrutinib, HM-71224, spebrutinib, BTKinhibitor (rheumatoid arthritis), Humanwell Healthcare/Wuxi AppTech,BMS-986142, TAK-020, ONO-4059, TAS-5315, ABBV-105, AC-0025, RN-486,CG-026806, GDC-0834; Cadherin-11 antagonists, such as RG-6125;Calcineurin inhibitors, such as HS-378, ciclosporin; Calcium channelinhibitors, such as RP-3128; Carbonic anhydrase inhibitors, such aspolmacoxib; Cathepsin K inhibitors, such as CRA-013783, T-5224, AM-3876,VEL-0230, NPI-2019; Cathepsin S inhibitors, such as MIV-247, AM-3876,RWJ-445380, NPI-2019; CCR1 chemokine antagonists, such as BX-471,BMS-817399, BI-638683, CCX-354, MLN-3701, MLN-3897, CP-481715,PS-375179; CCR2 chemokine antagonists, such as MK-0812, AZD-6942; CCR3gene modulators, such as CM-102; CCR5 chemokine antagonists, such asmaraviroc, OHR-118, NIBR-6465, AZD-5672, AZD-8566; CD126 antagonists,such as sarilumab; CD29 modulators, such as PF-06687234; CD3 modulators,such as otelixizumab; CD39 agonists, such as AAV5-CD39/CD73 (rheumatoidarthritis), Arthrogen; CD4 agonists, such as maraviroc; CD4 antagonists,such as tregalizumab, zanolimumab, MTRX-1011A, BW-4162W94, EP-1645,clenoliximab; CD40 ligand inhibitors, such as dapirolizumab pegol; CD40ligand receptor antagonists, such as BI-655064, anti-CD40-XTEN,teneliximab; CD40 ligand receptor modulators, such as CFZ-533; CD52antagonists, such as alemtuzumab; CD73 agonists, such as AAV5-CD39/CD73(rheumatoid arthritis), Arthrogen; CD79b modulators, such as MGD-010;CD80 antagonists, such as RhuDex, XENP-9523, ASP-2408, abataceptbiobetter; CD86 antagonists, such as ES-210, abatacept biosuperior,ASP-2408, XENP-9523; CD95 antagonists, such as DE-098, CS-9507; Celladhesion molecule inhibitors, such as natalizumab, alicaforsen,NPC-17923, TK-280, PD-144795; Choline kinase inhibitors, such as cholinekinase inhibitors (rheumatoid arthritis), UC San Diego; Clusterinstimulators, such as alemtuzumab; Complement C5 factor inhibitors, suchas eculizumab, antisense oligonucleotides (rheumatoid arthritis), LeidenUniversity Medical Center; Complement Factor stimulators, such asCM-101; C-reactive protein inhibitors, such as IB-RA (oral, rheumatoidarthritis), Innobioscience, ISIS-353512; CSF-1 antagonists, such asmasitinib, FPA-008, JNJ-27301937, JNJ-40346527, PLX-5622, CT-1578,PD-360324, JNJ-28312141; CXC10 chemokine ligand inhibitors, such as946414-98-8, BMS-936557; CXCR4 chemokine antagonists, such asplerixafor; Cyclin-dependent kinase inhibitor 1 inhibitors, such asCDK-1/2/5/7/9 inhibitors (cancer/tumorogenesis/rheumatoid arthritis),BioPatterns; Cyclin-dependent kinase-2 inhibitors, such as seliciclib,BP-14; Cyclin-dependent kinase-4 inhibitors, such as CDK-4/6 inhibitor(rheumatoid arthritis), Teijin; Cyclin-dependent kinase-5 inhibitors,such as BP-14; Cyclin-dependent kinase-6 inhibitors, such as CDK-4/6inhibitor (rheumatoid arthritis), Teijin; Cyclin-dependent kinase-7inhibitors, such as BP-14, seliciclib; Cyclin-dependent kinase-9inhibitors, such as BP-14, seliciclib; Cyclooxygenase 2 inhibitors, suchas celecoxib, etoricoxib, polmacoxib, laflunimus, etodolac, meloxicam,IB-RA (injectable, rheumatoid arthritis), Innobioscience, IB-RA (oral,rheumatoid arthritis), Innobioscience, SKLB-023, meloxicam, lumiracoxib;Cyclooxygenase 2 modulators, such as DRGT-46; Cyclooxygenase inhibitors,such as aceclofenac, diclofenac, imidazole salicylate, naproxcinod,naproxen etemesil, misoprostol with diclofenac, nabumetone, naproxenwith esomeprazole, naproxen with esomeprazole strontium, once-dailynaproxen (oral controlled release, pain), Alvogen, pelubiprofen,LY-210073, tenoxicam, licofelone, NS-398, bromfenac, L-746483,LY-255283, tenidap, tepoxalin, flobufen, ibuprofen, flurbiprofen,SKF-86002, SC-57666, WY-28342, CI-986, bermoprofen; Cytosolicphospholipase A2 inhibitors, such as AVX-002; Cytotoxic T-lymphocyteprotein-4 modulators, such as belatacept, ES-210; Cytotoxic T-lymphocyteprotein-4 stimulators, such as abatacept, abatacept biosimilar,BMS-188667; DHFR inhibitors, such as methotrexate, MPI-2505, MBP-Y003;Diamine acetyltransferase inhibitors, such as diminazene aceturate;Dihydroorotate dehydrogenase inhibitors, such as DHODH inhibitors(rheumatoid arthritis/autoimmune diseases), East China University ofScience and Technology, ASLAN-003, laflunimus, leflunomide, HWA-486,ABR-224050; Elongation factor 2 inhibitors, such as denileukin diftitox;Eotaxin 2 ligand inhibitors, such as CM-102; EP4 prostanoid receptorantagonists, such as CR-6086; Erythropoietin receptor agonists, such ascibinetide; Fas ligands, such as AP-300; FGF-2 ligand inhibitors, suchas RBM-007; FK506 binding protein-12 modulators, such as temsirolimus;Folate antagonists, such as methotrexate, MBP-Y003; Folate receptoragonists, such as folate receptor modulators (chimeric protein,cancer/rheumatoid arthritis), Proda Biotech; Folate receptor modulators,such as technetium (99mTc) etarfolatide; Fractalkine ligand inhibitors,such as E-6011; Fyn tyrosine kinase inhibitors, such as masitinib,laflunimus; G protein coupled receptor 15 antagonists, such as GPR15antagonists (rheumatoid arthritis/HIV-mediated enteropathy), Omeros;GABA A receptor modulators, such as laflunimus; Glucocorticoid agonists,such as prednisolone, fosdagrocorat; Glucocorticoid antagonists, such asREC-200; Glucocorticoid induced leucine zipper stimulators, such asART-G01; GM-CSF ligand inhibitors, such as namilumab, MORAb-022,lenzilumab; GM-CSF receptor antagonists, such as mavrilimumab; GM-CSFreceptor modulators, such as GSK-3196165; Growth regulated protein alphaligand inhibitors, such as T-5224; Hwith Kwith ATPase inhibitors, suchas naproxen with esomeprazole, naproxen with esomeprazole strontium,ketoprofen with omeprazole, KEO-25001, HC-1004, PN-40020; Histamine H4receptor antagonists, such as toreforant, GD-48; Histone deacetylaseinhibitors, such as givinostat, CHR-5154; Histone deacetylase-6inhibitors, such as CKD-506; HIV-1 gp120 protein inhibitors, such asmaraviroc; HLA class II antigen DQ-2 alpha modulators, such as NexVax2;HLA class II antigen inhibitors, such as HLA-DR1/DR4 inhibitors(rheumatoid arthritis), Provid; HLA class II antigen modulators, such asARG-301, recombinant T-cell receptor ligand (rheumatoid arthritis),Artielle; Hsp 70 family inhibitors, such as gusperimus trihydrochloride;Hypoxia inducible factor-1 inhibitors, such as 2-methoxyestradiol; IFNBgene stimulators, such as ART-102; I-kappa B kinase beta inhibitors,such as IMD-2560, IMD-0560; I-kappa B kinase inhibitors, such asbardoxolone methyl; IL-1 antagonists, such as rilonacept, IBPB-007-IL,antisense oligonucleotides (rheumatoid arthritis), Leiden UniversityMedical Center, recombinant human interleukin-1 receptor antagonist(rheumatoid arthritis), Shanghai Fudan-Zhangjiang Bio-Pharmaceutical;IL-10 agonists, such as peg-ilodecakin; IL-11 agonists, such asoprelvekin; IL-12 antagonists, such as ustekinumab, briakinumab, ddRNAitherapy (rheumatoid arthritis), Medistem/Benitec; IL-15 antagonists,such as AMG-714, BNZ-132-2; IL-17 antagonists, such as ixekizumab,secukinumab, KD-025; IL-17 receptor modulators, such as CNTO-6785; IL-2agonists, such as interleukin-2 follow-on biologic; IL-2 antagonists,such as IB-RA (injectable, rheumatoid arthritis), Innobioscience, IB-RA(oral, rheumatoid arthritis), Innobioscience, BNZ-132-2; IL-21antagonists, such as NN-8828, BNZ-132-2; IL-23 antagonists, such asustekinumab, briakinumab; IL-3 antagonists, such as anti-IL-3 mAbs(rheumatoid arthritis), University of Regensburg; IL-4 agonists, such asSER-130-AMI; IL-6 antagonists, such as olokizumab, clazakizumab,sirukumab, SA-237, tocilizumab, ALX-0061, FB-704A, OP-R003, peptide IL-6antagonist, MEDI-5117, T-5224, humanized anti-IL-6 mAh, tocilizumabbiosimilar, IL-6 neutralizing human antibodies, anti-IL6 antibody,RN-486, BLX-1002, AMG-220, FM-101, K-832, BLX-1025, esonarimod, TA-383;IL-6 receptor modulators, such as tocilizumab, tocilizumab biosimilar,RO-4877533; Immunoglobulin antagonists, such as iguratimod;Immunoglobulin G1 agonists, such as canakinumab, infliximab biobetter,infliximab biosimilar, BX-2922, STI-002, HF-1020; Immunoglobulin G1antagonists, such as YHB-1411-2; Immunoglobulin G1 modulators, such asCFZ-533, lenzilumab; Immunoglobulin G2 antagonists, such as denosumab;Immunoglobulin G2 modulators, such as PF-547659; Immunoglobulin gamma Fcreceptor II modulators, such as MGD-010; Immunoglobulin gamma Fcreceptor IIB antagonists, such as XmAb-5871; Immunoglobulin kappamodulators, such as lenzilumab; Immunoglobulin M antagonists, such asIB-RA (injectable, rheumatoid arthritis), Innobioscience, IB-RA (oral,rheumatoid arthritis), Innobioscience; Inducible nitric oxide synthaseinhibitors, such as SKLB-023; Inosine monophosphate dehydrogenaseinhibitors, such as mycophenolate mofetil; Insulin sensitizers, such asrosiglitazone, THR-0921, HE-3286, BLX-1002; Integrin alpha-1/beta-1antagonists, such as SAN-300; Integrin alpha-4/beta-1 antagonists, suchas natalizumab; Integrin antagonists, such as PEG-HM-3, CY-9652;Interferon beta ligands, such as recombinant interferon beta-1a, TA-383;Interferon gamma ligands, such as interferon gamma follow-on biologic;Interleukin 17A ligand inhibitors, such as ABT-122, bimekizumab,ABBV-257; Interleukin 17F ligand inhibitors, such as bimekizumab;Interleukin 23A inhibitors, such as guselkumab; Interleukin ligands,such as IBPB-007-IL; Interleukin receptor 17A antagonists, such asbrodalumab; Interleukin-1 beta ligand inhibitors, such as canakinumab,rilonacept, T-5224, gevokizumab, BLX-1002, LY-2189102, PMI-001, K-832,CDP-484; Interleukin-10 ligands, such as PF-06687234; Interleukin-2ligands, such as denileukin diftitox, recombinant interleukin-2,interleukin-2 follow-on biologic, recombinant human interleukin-2,interleukin-2 (injectable); Interleukin-4 ligands, such as Tetravil;Interleukin-6 ligand inhibitors, such as gerilimzumab, PF-4236921; Itktyrosine kinase inhibitors, such as ARN-4079; JAK tyrosine kinaseinhibitors, such as tofacitinib, SHR-0302, cerdulatinib, peficitinib,deuterated tofacitinib analog, SD-900, CVXL-0074; Jak1 tyrosine kinaseinhibitors, such as ABT-494, baricitinib, ruxolitinib, filgotinib,tofacitinib, itacitinib, peficitinib, NIP-585, CS-944X, YJC-50018,GLPG-0555, MRK-12; Jak2 tyrosine kinase inhibitors, such as baricitinib,ruxolitinib, CT-1578; JAK3 gene inhibitors, such as GBL-5b; Jak3tyrosine kinase inhibitors, such as decernotinib, tofacitinib,peficitinib, AC-0025, CS-944X, DNX-04042, MTF-003, ARN-4079, PS-020613;Jun N terminal kinase inhibitors, such as IQ-1S; KCNA voltage-gatedpotassium channel-3 modulators, such as MRAD-P1; Kelch like ECHassociated protein 1 modulators, such as dimethyl fumarate; Kit tyrosinekinase inhibitors, such as imatinib, masitinib; LanC like protein 2modulators, such as BT-11; LITAF gene inhibitors, such as GBL-5b;Lymphocyte function antigen-3 receptor antagonists, such as alefacept;Lyn tyrosine kinase inhibitors, such as masitinib; Macrophage mannosereceptor 1 modulators, such as technetium Tc 99m tilmanocept; MAdCAMinhibitors, such as PF-547659; MAP kinase modulators, such as SKLB-023;MAP3K2 gene inhibitors, such as GBL-5b; MAPKAPK5 inhibitors, such asGLPG-0259; Matrix metalloprotease inhibitors, such as GLPG-0259; MCL1gene inhibitors, such as seliciclib; MEK protein kinase inhibitors, suchas binimetinib, AD-GL0001; MEK-1 protein kinase inhibitors, such asbinimetinib; MEK-2 protein kinase inhibitors, such as binimetinib;Membrane copper amine oxidase inhibitors, such as BTT-1023, PRX-167700.vepalimomab; Metalloprotease-2 inhibitors, such as ERG-240;Metalloprotease-9 inhibitors, such as GS-5745, ERG-240; Midkine ligandinhibitors, such as CAB-102; Mitochondrial 10 kDa heat shock proteinstimulators, such as INV-103; mTOR complex 1 inhibitors, such aseverolimus; mTOR inhibitors, such as everolimus, temsirolimus; NAD ADPribosyltransferase stimulators, such as denileukin diftitox; NAMPT geneinhibitors, such as ART-D01; NF kappa B inhibitor stimulators, such asdenosumab; NFAT gene inhibitors, such as T-5224; NFE2L2 genestimulators, such as bardoxolone methyl; Nicotinic acetylcholinereceptor antagonists, such as RPI-78, RPI-MN; NK cell receptormodulators, such as masitinib; NKG2 A B activating NK receptorantagonists, such as monalizumab; NKG2 D activating NK receptorantagonists, such as NNC-0142-002; Nuclear erythroid 2-related factor 2stimulators, such as dimethyl fumarate; Nuclear factor kappa Binhibitors, such as bardoxolone methyl, IB-RA (injectable, rheumatoidarthritis), Innobioscience, dehydroxymethylepoxyquinomicin, HE-3286,IMD-0560, MP-42, tarenflurbil, VGX-1027, SKLB-023, SP-650003, MG-132,SIM-916, VGX-350, VGX-300, GIT-027, SP-100030, MLN-1145, NVP-IKK-005;Nuclear factor kappa B modulators, such as REM-1086; Nuclear factorkappa B p105 inhibitors, such as REM-1086; Opioid growth factor receptoragonists, such as metenkefalin acetate with tridecactide acetate,FAR-404; Opioid receptor delta antagonists, such as HS-378; Osteoclastdifferentiation factor antagonists, such as denosumab, cyclicpeptidomimetics (rheumatoid arthritis/osteoporosis), University ofMichigan; Osteoclast differentiation factor ligand inhibitors, such asdenosumab; Oxidoreductase inhibitors, such as etodolac, imidazolesalicylate; P2X7 purinoceptor agonists, such as givinostat; p38 MAPkinase alpha inhibitors, such as VX-745, BMS-582949 prodrugs,BMS-751324; p38 MAP kinase inhibitors, such as BCT-197, losmapimod,ARRY-797; PDE 4 inhibitors, such as apremilast; PDE 5 inhibitors, suchas PDE5 inhibitors (rheumatoid arthritis), University of Rochester; PDGFreceptor agonists, such as oprelvekin; PDGF receptor antagonists, suchas imatinib, masitinib; PDGF-B ligand inhibitors, such as SL-1026; PERKgene inhibitors, such as binimetinib; Phosphoinositide-3 kinase deltainhibitors, such as duvelisib, RP-6503, CT-732, INK-007, GNE-293;Phosphoinositide-3 kinase gamma inhibitors, such as duvelisib, RP-6503;Phospholipase A2 inhibitors, such as AVX-002, human secretedphospholipase A2 type IIA-integrin binding inhibiting peptides(rheumatoid arthritis/asthma/Alzheimer's disease/cancer), University ofCalifornia, Davis, AK-106, varespladib methyl, Ro-31-4493, BM-162353,Ro-23-9358, YM-26734; Platelet activating factor receptor antagonists,such as piperidone hydrochloridum; PPAR gamma agonists, such asrosiglitazone, THR-0921, rosiglitazone XR, etalocib; Programmed celldeath protein 1 modulators, such as INSIX RA; Prostaglandin D synthasestimulators, such as HF-0220; Protein arginine deiminase inhibitors,such as PAD inhibitors (rheumatoid arthritis), Leiden University MedicalCenter/LURIS; Protein tyrosine kinase inhibitors, such as leflunomide;PurH purine biosynthesis protein inhibitors, such as mycophenolatemofetil; Rho associated protein kinase 2 inhibitors, such as KD-025;Seprase inhibitors, such as anti-fibroblast-activation protein (FAP)antibody radiotracers (rheumatoid arthritis), Hoffmann-La Roche/RadboudUniversity; Signal transducer CD24 modulators, such as CD24-IgFc; Signaltransduction inhibitors, such as imatinib; Sodium glucose transporter-2inhibitors, such as THR-0921; Sphingosine 1 phosphate phosphatasemodulators, such as SIP modulators (oral, multiple sclerosis/ulcerativecolitis/rheumatoid arthritis), Akaal Pharma; STAT3 gene inhibitors, suchas bardoxolone methyl, vidofludimus; Superoxide dismutase stimulators,such as imisopasem manganese; SYK family tyrosine kinase inhibitors,such as MK-8457; Syk tyrosine kinase inhibitors, such as fostamatinib,entospletinib, KDDF-201110-06, HMPL-523, cerdulatinib, AB-8779, GS-9876,PRT-2607, CVXL-0074, CG-103065 and CG-026806; Syndecan-1 inhibitors,such as indatuximab ravtansine; T cell receptor antagonists, such as TCRinhibiting SCHOOL peptides (systemic/topical, rheumatoidarthritis/dermatitis/scleroderma), SignaBlok, CII modified peptide(rheumatoid arthritis), Peking University; T cell receptor modulators,such as ARG-301; T cell surface glycoprotein CD28 inhibitors, such asabatacept, belatacept, abatacept biosimilar, RhuDex, BMS-188667; T cellsurface glycoprotein CD28 stimulators, such as TAB-08; TAK1 bindingprotein modulators, such as epigallocatechin 3-gallate; Talinmodulators, such as short-form talin regulators (rheumatoid arthritis),KayteeBio; T-cell differentiation antigen CD6 inhibitors, such asitolizumab; T-cell surface glycoprotein CD8 inhibitors, such astregalizumab; Tenascin modulators, such as Tetravil; TGF beta agonists,such as tregalizumab; Thymulin agonists, such as Syn-1002; TLR-2antagonists, such as VB-201, P-13; TLR-4 antagonists, such as VB-201,P-13; TLR-9 antagonists, such as P-13; TNF alpha ligand inhibitors, suchas adalimumab biosimilarYHB-1411-2, adalimumab, infliximab, infliximabbiosimilar, recombinant humanized anti-TNF-alpha monoclonal antibody,certolizumab pegol, golimumab, ozoralizumab, AT-132, etanerceptbiosimilar, ISIS-104838, ISU-202, CT-P17, MB-612, Debio-0512, anti-TNFalpha human monoclonal antibody, infliximab biobetter, UB-721, KN-002,DA-3113, BX-2922, R-TPR-015, BOW-050, PF-06410293, CKD-760, CHS-1420,GS-071, ABP-710, STI-002, BOW-015, FKB-327, BAX-2200, HLX-03, BI-695501,CNTO-148, MYL-1401AABP-501, HOT-3010, BAX-2923, SCH-215596, ABT-D2E7,BAT-1406, XPro-1595, Atsttrin, SSS-07, golimumab biosimilar, TA-101,adalimumab follow-on biologic, BLX-1002, ABX-0401, TAQ-588, golimumabbiosimilar, TeHL-1, placulumab, PMI-001, tgAAV-TNFR:Fc, K-832,CYT-007-TNFQb, SSR-150106, PassTNF, Verigen, DOM-0200, DOM-0215,AME-527, anti-TNF-alpha mAh, GENZ-38167, BLX-1028, CYT-020-TNFQb,CC-1080, CC-1069; TNF alpha ligand modulators, such as MM-A01-01,CDP-571, camobucol; TNF antagonists, such as etanercept, certolizumabpegol, etanercept follow-on biologic, etanercept biosimilar, DNX-114,TNF antagonist with IL-12 antagonist (rheumatoid arthritis), Universityof Oxford, BN-006, SCB-131, pegsunercept, GBL-5b, ACE-772, onercept,DE-096, PN-0615, lenercept, ITF-1779, MDL-201112, BAX-2200, SCB-808,DA-3853, HD-203; TNF gene inhibitors, such as GIBH-R-001-2; TNF receptormodulators, such as recombinant TNF receptor 2-Fc fusion protein mutant,T-0001, tgAAV-TNFR:Fc; TNFSF11 gene inhibitors, such as denosumab;Transcription factor p65 inhibitors, such as REM-1086; Transcriptionfactor RelB inhibitors, such as REM-1086; Transferrin modulators, suchas methotrexate, MBP-Y003; Tumor necrosis factor 13C receptorantagonists, such as VAY-736; Tumor necrosis factor 15 ligandinhibitors, such as anti-TL1A antibodies (rheumatoidarthritis/inflammatory bowel disease), NIAMS; Tumor necrosis factorligand 13 inhibitors, such as atacicept; Tumor necrosis factor ligandinhibitors, such as ABBV-257, etanercept biosimilar, ABT-122; Type IIL-1 receptor antagonists, such as anakinra, anakinra biosimilar,anakinra follow-on biologic, AXXO; Type I TNF receptor antagonists, suchas NM-9405; Type II TNF receptor modulators, such as etanercept,SCB-131, etanercept biosimilar, etanercept follow-on biologic, BAX-2200,SCB-808, LBEC-0101, DMB-3853, DWP-422, BT-D001, DA-3853; UnspecifiedGPCR agonists, such as NCP-70X; VEGF receptor antagonists, such as2-methoxyestradiol and NSC-650853, SL-1026; VEGF-2 receptor antagonists,such as CG-026806; VEGF-2 receptor modulators, such as VEGFR2neutralizing antibody (rheumatoid arthritis), University of Rochester;VEGF-B ligand inhibitors, such as CSL-346; X-linked inhibitor ofapoptosis protein inhibitors, such as IAP inhibitors (oral),Pharmascience; and Zap70 tyrosine kinase inhibitors, such as MK-8457,CT-5332.

Combinations for Metabolic Diseases or Conditions

Examples of metabolic disorders include, without limitation, diabetes,including type I and type II diabetes, metabolic syndrome, dyslipidemia,obesity, glucose intolerance, hypertension, elevated serum cholesterol,and elevated triglycerides. Examples of therapeutic agents used to treatmetabolic disorders include antihypertensive agents and lipid loweringagents. Additional therapeutic agents used to treat metabolic disordersinclude insulin, sulfonylureas peroxisome proliferator activatedreceptor gamma (PPAR-γ) agonists, such as thiazolidinediones such asPioglitazones, biguanides, alpha-glucosidase inhibitors, Vitamin E andincretin mimetics. Thus, one aspect of the disclosure is a method oftreating a metabolic disease comprising administering a compound of thedisclosure in combination with one or more compounds useful for thetreatment of metabolic diseases to a subject, particularly a humansubject, in need thereof.

Pharmaceutical Compositions

While it is possible for the active ingredients to be administered aloneit may be preferable to present them as pharmaceutical formulations(compositions). The formulations, both for veterinary and for human use,of the invention comprise at least one active ingredient, as abovedefined, together with one or more acceptable carriers therefor andoptionally other therapeutic ingredients. The carrier(s) must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and physiologically innocuous to the recipientthereof.

The formulations include those suitable for the foregoing administrationroutes. The formulations may conveniently be presented in unit dosageform and may be prepared by any of the methods well known in the art ofpharmacy. Techniques and formulations generally are found in Remington'sPharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methodsinclude the step of bringing into association the active ingredient withinactive ingredients (e.g., a carrier, pharmaceutical excipient, etc.)which constitutes one or more accessory ingredients. In general theformulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both, and then, if necessary, shaping the product.

In certain embodiments, formulations suitable for oral administrationare presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient.

In certain embodiments, the pharmaceutical formulations include one ormore compounds of the invention together with one or morepharmaceutically acceptable carriers or excipients and optionally othertherapeutic agents. Pharmaceutical formulations containing the activeingredient may be in any form suitable for the intended method ofadministration. When used for oral use for example, tablets, troches,lozenges, aqueous or oil suspensions, dispersible powders or granules,emulsions, hard or soft capsules, syrups or elixirs may be prepared.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation. Tabletscontaining the active ingredient in admixture with non-toxicpharmaceutically acceptable excipient which are suitable for manufactureof tablets are acceptable. These excipients may be, for example, inertdiluents, such as calcium or sodium carbonate, lactose, lactosemonohydrate, croscarmellose sodium, povidone, calcium or sodiumphosphate; granulating and disintegrating agents, such as maize starch,or alginic acid; binding agents, such as cellulose, microcrystallinecellulose, starch, gelatin or acacia; and lubricating agents, such asmagnesium stearate, stearic acid or talc. Tablets may be uncoated or maybe coated by known techniques including microencapsulation to delaydisintegration and adsorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearatealone or with a wax may be employed.

The amount of active ingredient that is combined with the inactiveingredients to produce a dosage form will vary depending upon the hosttreated and the particular mode of administration. For example, in someembodiments, a dosage form for oral administration to humans containsapproximately 1 to 1000 mg of active material formulated with anappropriate and convenient amount of carrier material (e.g., inactiveingredient or excipient material). In certain embodiments, the carriermaterial varies from about 5 to about 95% of the total compositions(weight:weight). In some embodiments, the pharmaceutical compositionsdescribed herein contain about 1 to 800 mg, 1 to 600 mg, 1 to 400 mg, 1to 200 mg, 1 to 100 mg or 1 to 50 mg of the compound of Formula I, or apharmaceutically acceptable salt thereof. In some embodiments, thepharmaceutical compositions described herein contain not more than about400 mg of the compound of Formula I. In some embodiments, thepharmaceutical compositions described herein contain about 100 mg of thecompound of Formula I, or a pharmaceutically acceptable salt thereof.

It should be understood that in addition to the ingredients particularlymentioned above the formulations disclosed herein may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

Veterinary compositions comprising at least one active ingredient asabove defined together with a veterinary carrier are further provided.

Veterinary carriers are materials useful for the purpose ofadministering the composition and may be solid, liquid or gaseousmaterials which are otherwise inert or acceptable in the veterinary artand are compatible with the active ingredient. These veterinarycompositions may be administered orally, parenterally or by any otherdesired route.

Effective dose of active ingredient depends at least on the nature ofthe condition being treated, toxicity, whether the compound is beingused prophylactically (lower doses), the method of delivery, and thepharmaceutical formulation, and will be determined by the clinicianusing conventional dose escalation studies.

Routes of Administration

One or more compounds of Formula I (herein referred to as the activeingredients), or a pharmaceutically acceptable salt thereof, areadministered by any route appropriate to the condition to be treated.Suitable routes include oral, rectal, nasal, topical (including buccaland sublingual), vaginal and parenteral (including subcutaneous,intramuscular, intravenous, intradermal, intrathecal and epidural), andthe like. It will be appreciated that the preferred route may vary withfor example the condition of the recipient. An advantage of thecompounds of this invention is that they are orally bioavailable and canbe dosed orally. Accordingly, in one embodiment, the pharmaceuticalcompositions described herein are oral dosage forms. In certainembodiments, the pharmaceutical compositions described herein are oralsolid dosage forms.

Formulation Example 1

Hard gelatin capsules containing the following ingredients are prepared:

Ingredient Quantity (mg/capsule) Active Ingredient 30.0 Starch 305.0Magnesium stearate 5.0

The above ingredients are mixed and filled into hard gelatin capsules.

Formulation Example 2

A tablet Formula is prepared using the ingredients below:

Ingredient Quantity (mg/tablet) Active Ingredient 25.0 Cellulose,microcrystalline 200.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

The components are blended and compressed to form tablets.

Formulation Example 3

A dry powder inhaler formulation is prepared containing the followingcomponents:

Ingredient Weight % Active Ingredient 5 Lactose 95

The active ingredient is mixed with the lactose and the mixture is addedto a dry powder inhaling appliance.

Formulation Example 4

Tablets, each containing 30 mg of active ingredient, are prepared asfollows:

Ingredient Quantity (mg/tablet) Active Ingredient 30.0 mg Starch 45.0 mgMicrocrystalline cellulose 35.0 mg Polyvinylpyrrolidone 4.0 mg (as 10%solution in sterile water) Sodium carboxymethyl starch 4.5 mg Magnesiumstearate 0.5 mg Talc 1.0 mg Total 120 mg

The active ingredient, starch and cellulose are passed through a No. 20mesh U.S. sieve and mixed thoroughly. The solution ofpolyvinylpyrrolidone is mixed with the resultant powders, which are thenpassed through a 16 mesh U.S. sieve. The granules so produced are driedat 50° C. to 60° C. and passed through a 16 mesh U.S. sieve. The sodiumcarboxymethyl starch, magnesium stearate and talc, previously passedthrough a No. 30 mesh U.S. sieve, are then added to the granules which,after mixing, are compressed on a tablet machine to yield tablets eachweighing 120 mg.

Formulation Example 5

Suppositories, each containing 25 mg of active ingredient are made asfollows:

Ingredient Amount Active Ingredient   25 mg Saturated fatty acidglycerides to 2,000 mg

The active ingredient is passed through a No. 60 mesh U.S. sieve andsuspended in the saturated fatty acid glycerides previously melted usingthe minimum heat necessary. The mixture is then poured into asuppository mold of nominal 2.0 g capacity and allowed to cool.

Formulation Example 6

Suspensions, each containing 50 mg of active ingredient per 5.0 mL doseare made as follows:

Ingredient Amount Active Ingredient 50.0 mg Xanthan gum 4.0 mg Sodiumcarboxymethyl cellulose (11%) Microcrystalline cellulose (89%) 50.0 mgSucrose 1.75 g Sodium benzoate 10.0 mg Flavor and Color q.v. Purifiedwater to 5.0 mL

The active ingredient, sucrose and xanthan gum are blended, passedthrough a No. 10 mesh U.S. sieve and then mixed with a previously madesolution of the microcrystalline cellulose and sodium carboxymethylcellulose in water. The sodium benzoate, flavor and color are dilutedwith some of the water and added with stirring. Sufficient water is thenadded to produce the required volume.

Formulation Example 7

A subcutaneous formulation may be prepared as follows:

Ingredient Quantity Active Ingredient 5.0 mg Corn Oil 1.0 mL

Formulation Example 8

An injectable preparation is prepared having the following composition:

Ingredients Amount Active ingredient 2.0 mg/mL Mannitol, USP 50 mg/mLGluconic acid, USP q.s. (pH 5-6) water (distilled, sterile) q.s. to 1.0mL Nitrogen Gas, NF q.s.

Formulation Example 9

A topical preparation is prepared having the following composition:

Ingredients grams Active ingredient 0.2-10 Span 60 2.0 Tween 60 2.0Mineral oil 5.0 Petrolatum 0.10 Methyl paraben 0.15 Propyl paraben 0.05BHA (butylated hydroxy anisole) 0.01 Water q.s. to 100

All of the above ingredients, except water, are combined and heated to60° C. with stirring. A sufficient quantity of water at 60° C. is thenadded with vigorous stirring to emulsify the ingredients and water thenadded q.s. 100 g.

Formulation Example 10

Ingredient Weight Range % Active ingredient 50-95 Microcrystallinecellulose (filler)  1-35 Methacrylic acid copolymer  1-35 Sodiumhydroxide 0.1-1.0 Hydroxypropyl methylcellulose 0.5-5.0 Magnesiumstearate 0.5-5.0

Sustained release formulations of this disclosure may be prepared asfollows: compound and pH-dependent binder and any optional excipientsare intimately mixed (dry-blended). The dry-blended mixture is thengranulated in the presence of an aqueous solution of a strong base whichis sprayed into the blended powder. The granulate is dried, screened,mixed with optional lubricants (such as talc or magnesium stearate) andcompressed into tablets. Preferred aqueous solutions of strong bases aresolutions of alkali metal hydroxides, such as sodium or potassiumhydroxide, preferably sodium hydroxide, in water (optionally containingup to 25% of water-miscible solvents such as lower alcohols).

The resulting tablets may be coated with an optional film-forming agent,for identification, taste-masking purposes and to improve ease ofswallowing. The film forming agent will typically be present in anamount ranging from between 2% and 4% of the tablet weight. Suitablefilm-forming agents are well known to the art and include hydroxypropylmethylcellulose, cationic methacrylate copolymers (dimethylaminoethylmethacrylate/methyl-butyl methacrylate copolymers—Eudragit® E—Röhm.Pharma) and the like. These film-forming agents may optionally containcolorants, plasticizers and other supplemental ingredients.

The compressed tablets preferably have a hardness sufficient towithstand 8 Kp compression. The tablet size will depend primarily uponthe amount of compound in the tablet. The tablets will include from 300to 1100 mg of compound free base. Preferably, the tablets will includeamounts of compound free base ranging from 400-600 mg, 650-850 mg and900-1100 mg.

In order to influence the dissolution rate, the time during which thecompound containing powder is wet mixed is controlled. Preferably thetotal powder mix time, i.e., the time during which the powder is exposedto sodium hydroxide solution, will range from 1 to 10 minutes andpreferably from 2 to 5 minutes. Following granulation, the particles areremoved from the granulator and placed in a fluid bed dryer for dryingat about 60° C.

Formulation Example 11

A tablet Formula Is prepared using the ingredients below:

Ingredient Quantity (mg/tablet) Active Ingredient 300.0 Cellulose,microcrystalline 100.0 Colloidal silicon dioxide 10.0 Stearic acid 5.0

The components are blended and compressed to form tablets.

EXAMPLES

The following examples are included to demonstrate specific embodimentsof the disclosure. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques to function well in the practice of the disclosure, and thuscan be considered to constitute specific modes for its practice.However, those of skill in the art should, in light of the presentdisclosure, appreciate that many changes can be made in the specificembodiments which are disclosed and still obtain a like or similarresult without departing from the spirit and scope of the disclosure.

LIST OF ABBREVIATIONS AND ACRONYMS

Abbreviation Meaning ° C. Degree Celsius Ac Acetyl aq. Aqueous ATPAdenosine triphosphate B₂Pin₂ Bis(pinacolato)diboron BOCtert-Butoxycarbonyl Br Broad BSA Bovine serum albumin d Doublet DCMDichloromethane dd Doublet of doublets ddd Doublet of doublet ofdoublets DIPEA N,N-Diisopropylethylamine (Hünig's Base) DMADimethylacetamide DME 1,2-Dimethoxyethane DMF Dimethylformamide DMSODimethylsulfoxide dt Doublet-triplet DTT Dithiothreitol (Cleland'sreagent) EC₅₀ The half maximal effective concentration EDC1-(3-dimethylaminopropyl)-3-ethylcarbodiimide EDTAEthylenediaminetetraacetic acid EGFR Epidermal growth factor receptor EqEquivalents ES/MS Electrospray mass spectrometry Et Ethyl EtOAc Ethylacetate EtOH Ethanol (Ethyl alcohol) FBS Fetal bovine serum g Grams HATU1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate HEPES 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid HCl Hydrochloric acid HPLC High pressure liquidchromatography Hrs Hours HTRF ® Homogeneous time resolved fluorescence,a registered trademark of Cisbio Bioassays, parc marcel boiteux 30200codolet, France Hz Hertz IBD Inflammatory bowel disease IC₅₀Half-maximal inhibitory concentration i-pr Isopropyl J Coupling constant(MHz) K₃PO₄ Tripotasium phosphate KOtBu Potassium tert-butoxide KOAcPotassium Acetate LCMS Liquid chromatography-mass spectrometry Li HMDSLithium bis(trimethylsilyl)amide LiOH Lithium hydroxide LiI Lithiumiodide LPS Lipopolysaccharide M Molar m multiplet M+ Mass peak M + H+Mass peak plus hydrogen Me Methyl MeCN Acetonitrile MeOH Methanol(Methyl alcohol) MeLi Methyllithium MeMgX Methylmagnesium halide(Grignard reagent), where X is Fluoro, Chloro, Bromo or Iodo Me₆Sn₂Hexamethyldistannane (hexamethylditin) mg Milligram MgSO₄ Magnesiumsulfate MHz Megahertz Min Minute ml/mL Milliliter mM Millimolar mmolMillimole MS Mass spectroscopy MsCl Mesyl chloride NBSN-Bromosuccinimide n- Normal nBu/Bu n-Butyl (normal Butyl) n-BuLin-Butyl Lithium NaH Sodium hydride NaHCO₃ Sodium bicarbonate NaN₃ Sodiumazide Na₃PO₄ Trisodium phosphate Na₂SO₄ Sodium sulfate nL Nanoliter nmNanometer NMP 1-methylpyrrolidin-2-one NMR Nuclear magnetic resonanceNP-40 Nonyl phenoxypolyethoxylethanol Pd-PEPPSI ™ -IPent[1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride Pen-StrepPenicillin-Streptomycin (5,000 units of penicillin G sodium salt, and5,000 μg streptomycin sulfate in 0.85% saline) Ph Phenyl q Quartet q.s.Quantity sufficient to achieve a stated function RP Reverse phase RPMIRoswell Park Memorial Institute medium Rt Room temperature s Singletsat. Saturated Selectfluor ® 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis (a trademark of Air Products andChemicals) SFC Supercritical fluid chromatography SiliaMetS ® ThiolSilica-based Palladium scavenger, registered trademark of Silicycle TTriplet THF Tetrahydrofuran TFA Trifluoroacetic acid XPhos Pd G3(2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′- biphenyl)]palladium(II)methanesulfonate

1. Comparative Example A

Comparative Example A is shown as Example 193 in International PatentApplication PCT/US2016/038861, published as WO 2016/210036 A1. Thestructure of Comparative Example A is:

2. Synthesis of Intermediates Preparation of Intermediate I-1

3,3-Diethoxy-2-formylpropionitrile Potassium Salt (I-1C)

To a stirred solution of 3,3-diethoxypropane-nitrile (I-1A, 283.80 g,1.98 moles) and methyl formate (I-1B, 148.80 g, 2.48 moles) in anhydrousTHE (1.1 L) at 10° C. was added 1.0 M potassium tert-butoxide in THE(2.2 L, 2.2 moles). The temperature was maintained in the range of 10°C. to 15° C. throughout the 45 minute addition. Following the addition,the resulting slurry was stirred for 2 hours at ambient temperature.Hexane (400 mL) was then added and stirring was continued for another 20min. Tire slurry was filtered and the cake washed with 1/1 hexanes/THFand dried overnight at 60° C. in a vacuum oven to provide I-1C. ¹H-NMR(CD₃OD) was consistent with the desired structure.

Pyrrolo[1,2-b]pyridazine-3-carbonitrile (I-1E)

A stirred suspension of 3,3-diethoxy-2-formylpropionitrile potassiumsalt (I-1C, 5.10 g, 24.36 mmol) was cooled to 0° C., and concentratedHCl (7.11 mL, 85.26 mmol) was added dropwise at such a rate that theinternal temperature of the reaction did not go above 20° C. Afteraddition was complete, the reaction was stirred at room temperature for20 minutes. To this reaction mixture was added a solution of1-aminopyrrole (I-1D, 1.00 g, 12.18 mmol) in methanol (4.0 mL). Afteraddition, the reaction mixture was refluxed at 90° C. for 2 hours. Whenheating was complete, the reaction was cooled to room temperature andconcentrated to about half of the original volume. Saturated aqueoussodium bicarbonate was added carefully to the resulting residue untilbubbling stopped. The solution was extracted with two portions of ethylacetate. The combined organic layers were dried over sodium sulfate,filtered, concentrated in vacuo, and the resulting residue was purifiedby silica gel chromatography (eluent: EtOAc/hexanes) to provide I-1E.

1H NMR (400 MHz, Chloroform-d) δ 8.16-8.03 (m, 2H), 7.93 (ddd, J=2.6,1.4, 0.6 Hz, 1H), 7.04 (dd, J=4.5, 2.7 Hz, 1H), 6.84 (dd, J=4.6, 1.4 Hz,1H).

7-bromopyrrolo[1,2-b]pyridazine-3-carbonitrile (I-1F)

To a solution of pyrrolo[1,2-b]pyridazine-3-carbonitrile (I-1E, 840.0mg, 5.9 mmol) in MeCN (30 mL) at room temperature was addedN-bromosuccinimide in one portion. The reaction was stirred at roomtemperature for 30 minutes then poured into saturated aqueous sodiumbicarbonate. The solution was concentrated in vacuo to remove theacetonitrile. The resulting aqueous layer was extracted with threeportions of EtOAc. The combined organic layers were dried over sodiumsulfate, filtered, concentrated in vacuo, and purified by silica gelchromatography (eluent: EtOAc/hexanes) to provide I-1F.

1H NMR (400 MHz, Chloroform-d) δ 8.28 (d, J=2.1 Hz, 1H), 8.10 (d, J=2.1Hz, 1H), 7.12 (d, J=4.8 Hz, 1H), 6.93 (d, J=4.8 Hz, 1H).

7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(I-1)

A microwave vial was charged with7-bromopyrrolo[1,2-b]pyridazine-3-carbonitrile (I-1F, 416.5 mg, 1.9mmol), bis(pinacolato)diboron (762.1 mg, 3.0 mmol), potassium acetate(552.3 mg, 5.6 mmol), and bis(triphenylphosphine)palladium(II)dichloride (65.8 mg, 0.094 mmol). Dioxane (8.0 mL) and DMF (4.0 mL) wereadded, and the reaction mixture was degassed with bubbling argon for 2minutes. The vial was sealed and the reaction was heated at 120° C. in amicrowave reactor for 60 minutes. After cooling, the reaction mixturewas filtered and concentrated in vacuo. The resulting residue waspartitioned between EtOAc and water. The aqueous layer was extractedwith a second portion of EtOAc, and the combined organic layers weredried over sodium sulfate, filtered through a plug of Celite, andconcentrated in vacuo. The resulting residue was purified by silica gelchromatography (eluent: EtOAc/hexanes) to provide I-1.

1H NMR (400 MHz, Chloroform-d) δ 8.31 (d, J=2.3 Hz, 1H), 8.14 (d, J=2.2Hz, 1H), 7.52 (d, J=4.6 Hz, 1H), 6.84 (d, J=4.6 Hz, 1H), 1.41 (s, 12H).

Preparation of Intermediate I-2

6-bromo-4-chloronicotinic acid. To a solution of methyl6-bromo-4-chloronicotinate (15 g, 59.89 mmol) in methanol (240 mL) wasadded lithium hydroxide (2.93 g, 119.77 mmol) in water (68 mL). Thesolution was heated to 43° C. overnight and subsequently cooled to roomtemperature. Aqueous hydrochloric acid (1M, 120 mL) was added andvolatiles were removed in vacuo. The resulting slurry was filtered andwashed with H₂O to provide 6-bromo-4-chloronicotinic acid.

ES/MS: 238.0 (M+H⁺).

1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.03 (s, 1H).

(R)-6-bromo-4-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide.To a solution of 6-bromo-4-chloronicotinic acid (3 g, 12.69 mmol) in DMF(42 mL) was added HATU (6.27 g, 16.49 mmol),(R)-4-amino-3-fluoro-2-methylbutan-2-ol hydrochloride (2.4 g, 15.23mmol), and N,N-Diisopropylethylamine (5.62 ml, 32.26 mmol). Theresulting solution was stirred at room temperature overnight andsubsequently diluted with ethyl acetate. The organic solution was washedwith saturated aqueous lithium chloride (3 times), then dried overNa₂SO₄, and then concentrated. The residue was purified by silica gelchromatography (eluent: EtOAc/hexanes) to provide(R)-6-bromo-4-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide.

ES/MS: 341.1 (M+H⁺).

1H NMR (400 MHz, DMSO-d₆) δ 8.88 (t, J=5.5 Hz, 1H), 8.41 (s, 1H), 8.01(s, 1H), 4.82 (s, 1H), 4.28 (ddd, J=49.3, 9.4, 2.0 Hz, 1H), 3.84-3.63(m, 1H), 3.40-3.22 (m, 1H), 1.13 (d, J=7.0 Hz, 6H).

(R)-4-chloro-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(1-5). To a solution of(R)-6-bromo-4-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(0.2 g, 0.59 mmol) in DME (3.9 mL) was added7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(0.24 g, 0.9 mmol), XPhos Pd G3 (0.05 g, 0.06 mmol), and aqueouspotassium phosphate tribasic (2M, 0.59 mL, 1.18 mmol). The resultingsolution was degassed with argon and heated to 120° C. for 12 minutes ina microwave reactor. The crude reaction mixture was purified by silicagel chromatography (eluent: EtOAc/hexanes) to provide(R)-4-chloro-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide.

ES/MS: 402.2 (M+H⁺).

3. Example Procedures and Compound Examples Procedure 1: Example 1(R)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(methylamino)nicotinamide

Methyl 6-chloro-4-(methylamino)nicotinate: To a solution of methyl4,6-dichloronicotinate (0.5 g, 2.43 mmol) and methylamine hydrochloride(0.82 g, 12.16 mmol) in acetonitrile (10 mL) and water (0.3 mL) wasadded 1,8-diazabicyclo(5.4.0)undec-7-ene (1.8 ml, 12.04 mmol). Theresulting solution was stirred at room temperature for 3 hours. Thesolution was concentrated to dryness in vacuo and diluted with ethylacetate. The resulting solution was washed with water and aqueous sodiumchloride. The resulting organic layer was dried over sodium sulfate andconcentrated in vacuo. The resulting material was purified normal phaseSiO₂ chromatography (eluent: ethyl acetate/hexanes) to provide thedesired product.

ES/MS: 201.180 (M+H⁺).

6-Chloro-4-(methylamino)nicotinic acid: To a solution of methyl6-chloro-4-(methylamino)nicotinate (0.38 g, 1.92 mmol) in MeOH (10 mL),THF (5 mL), and water (5 mL) was added lithium hydroxide (0.12 g, 5.01mmol). The solution was stirred at room temperature for 18 h,neutralized with HCl (1N, 5 mL), and concentrated to dry in vacuo. Theresulting crude material was used in the subsequent step.

ES/MS: 187.070 (M+H⁺).

(R)-6-Chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(methylamino)nicotinamide:To a solution of 6-chloro-4-(methylamino)nicotinic acid (0.36 g, 1.92mmol) and (R)-4-amino-3-fluoro-2-methylbutan-2-ol (0.31 g, 2.56 mmol) inDMF (10 mL) was added HATU (0.97 g, 2.55 mmol) andN,N-Diisopropylethylamine (1.5 ml, 8.61 mmol). The resulting solutionwas stirred at room temperature for 1 hour and diluted with ethylacetate. The solution was washed with 5% aqueous lithium chloride (3×),dried over sodium sulfate, and concentrated in vacuo. The resultingmaterial was purified normal phase SiO₂ chromatography (eluent: ethylacetate/hexanes) to provide the desired product.

ES/MS: 290.472 (M+H⁺).

(R)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(methylamino)nicotinamide:To a solution of(R)-6-chloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(methylamino)nicotinamide(30 mg, 0.10 mmol),7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(39 mg, 0.15 mmol) and Xphos Pd G3 (9 mg, 0.011 mmol) in DME (1 mL) wasadded aqueous potassium phosphate (2M, 0.10 mL, 0.20 mmol). Theresulting solution was degassed with argon for 2 min and heating undermicrowave conditions for 20 min at 120° C. The reaction mixture wasfiltered and the resulting solids were washed with DMF. The filtrateswere then concentrated in vacuo and the crude material was purified byRP-HPLC (eluent: water/MeCN*0.1% TFA) to yield the product as atrifluoroacetate salt.

ES/MS: 397.283 (M+H⁺).

1H NMR (400 MHz, Methanol-d4) δ 8.75 (d, J=2.2 Hz, 1H), 8.66 (d, J=2.2Hz, 1H), 8.51 (s, 1H), 8.02 (d, J=5.1 Hz, 1H), 7.76 (s, 1H), 7.21 (d,J=5.1 Hz, 1H), 4.42 (ddd, J=49.0, 9.3, 2.1 Hz, 1H), 3.93 (ddd, J=36.4,14.5, 2.2 Hz, 1H), 3.48 (ddd, J=16.2, 14.5, 9.4 Hz, 1H), 3.19 (s, 3H),1.28 (d, J=1.7 Hz, 6H).

Procedure 2: Example 2(R)-4-((cyanomethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide

(R)-6-chloro-4-((cyanomethyl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide:To a slurry of(R)-4,6-dichloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (100mg, 0.34 mmol) and aminoacetonitrile hydrochloride (47.03 mg, 0.51 mmol)in DMA (1 mL) was added N,N-diisopropylethylamine (0.2 mL, 1.12 mmol).The resulting solution was then heated under microwave conditions for 30min at 150° C. Additional aminoacetonitrile hydrochloride (47.03 mg,0.51 mmol) and N,N-diisopropylethylamine (0.2 mL, 1.12 mmol) were addedand the reaction was heated under thermal conditions for 16 hours at130° C. The solution was cooled to room temperature and diluted withethyl acetate. The resulting slurry was filtered and the solid waswashed with EtOAc. The resulting filtrates were combined and washed withaqueous ammonia chloride. The resulting organic layer was dried overmagnesium sulfate and concentrated in vacuo. The resulting material waspurified normal phase SiO₂ chromatography (eluent: ethylacetate/hexanes) to provide the desired product.

ES/MS: 315.159 (M+H⁺).

(R)-4-((cyanomethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide:To a solution of(R)-6-chloro-4-((cyanomethyl)amino)-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide(53 mg, 0.17 mmol),7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[1,2-b]pyridazine-3-carbonitrile(68 mg, 0.25 mmol) and Xphos Pd G3 (16 mg, 0.019 mmol) in DME (2 mL) wasadded aqueous potassium phosphate (2M, 0.17 mL, 0.34 mmol). Theresulting solution was degassed with argon for 2 min and heating undermicrowave conditions for 20 min at 120° C. The reaction mixture wasfiltered and the resulting solids were washed with DMF and MeOH. Thefiltrates were then concentrated in vacuo and the crude material waspurified by RP-HPLC (eluent: water/MeCN*0.1% TFA) to yield the productas a trifluoroacetate salt. The material was further purified by normalphase SiO₂ chromatography (eluent: methanol/dichloromethane) andlyophilized from acetonitrile and water (0.1% trifluoroacetic acid) toprovide the desired product.

ES/MS: 422.250 (M+H⁺).

1H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J=2.2 Hz, 1H), 8.70 (d, J=2.0Hz, 2H), 8.10 (d, J=5.1 Hz, 1H), 8.05 (s, 1H), 7.25 (d, J=5.1 Hz, 1H),4.73 (s, 2H), 4.46 (ddd, J=49.1, 9.4, 2.2 Hz, 1H), 3.98 (ddd, J=36.6,14.5, 2.2 Hz, 1H), 3.60-3.41 (m, 1H), 1.31 (d, J=1.7 Hz, 6H).

Procedure 3: Example 34-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide

4-(((R)-1-amino-1-oxopropan-2-yl)amino)-6-chloro-N—((R)-2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide:To a slurry of(R)-4,6-dichloro-N-(2-fluoro-3-hydroxy-3-methylbutyl)nicotinamide (200mg, 0.68 mmol) and (R)-2-aminopropanamide hydrochloride (172 mg, 1.38mmol) in DMA (3 mL) was added N,N-diisopropylethylamine (0.6 mL, 3.37mmol). The resulting solution was then heated under microwave conditionsfor 60 min at 150° C. The resulting material was purified by RP-HPLC(eluent: water/MeCN*0.1% TFA) to yield the product as a trifluoroacetatesalt.

ES/MS: 347.521 (M+H⁺).

TABLE 1 Compounds ES/MS Compound m/z Procedure Name 1 397.3 1(R)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3-methylbutyl)-4-(methylamino)nicotinamide 2 422.3 2(R)-4-((cyanomethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide 3436.4 3 4-(((R)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide4 436.3 3 4-(((S)-1-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide5 450.4 3 4-(((R)-1-cyanopropyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide6 450.3 3 4-(((S)-1-cyanopropyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-((R)-2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide7 436.5 2 (R)-4-((2-cyanoethyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide 8450.7 2 (R)-4-((3-cyanopropyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide 9450.5 3 (R)-4-((2-cyanopropan-2-yl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide 10448.5 2 (R)-4-((1-cyanocyclopropyl)amino)-6-(3-cyanopyrrolo[1,2-b]pyridazin-7-yl)-N-(2-fluoro-3-hydroxy-3- methylbutyl)nicotinamide

TABLE 2 NMR Data for Exemplified Compounds Compound 1H-NMR 1 1H NMR (400MHz, Methanol-d4) δ 8.75 (d, J = 2.2 Hz, 1H), 8.66 (d, J = 2.2 Hz, 1H),8.51 (s, 1H), 8.02 (d, J = 5.1 Hz, 1H), 7.76 (s, 1H), 7.21 (d, J = 5.1Hz, 1H), 4.42 (ddd, J = 49.0, 9.3, 2.1 Hz, 1H), 3.93 (ddd, J = 36.4,14.5, 2.2 Hz, 1H), 3.48 (ddd, J = 16.2, 14.5, 9.4 Hz, 1H), 3.19 (s, 3H),1.28 (d, J = 1.7 Hz, 6H) 2 1H NMR (400 MHz, Methanol-d4) δ 8.79 (d, J =2.2 Hz, 1H), 8.70 (d, J = 2.0 Hz, 2H), 8.10 (d, J = 5.1 Hz, 1H), 8.05(s, 1H), 7.25 (d, J = 5.1 Hz, 1H), 4.73 (s, 2H), 4.46 (ddd, J = 49.1,9.4, 2.2 Hz, 1H), 3.98 (ddd, J = 36.6, 14.5, 2.2 Hz, 1H), 3.60-3.41 (m,1H), 1.31 (d, J = 1.7 Hz, 6H). 3 1H NMR (400 MHz, Methanol-d4) δ 8.79(d, J = 2.1 Hz, 1H), 8.73 (s, 1H), 8.71 (d, J = 2.1 Hz, 1H), 8.09 (d, J= 5.1 Hz, 1H), 8.07 (s, 1H), 7.26 (d, J = 5.1 Hz, 1H), 5.15 (q, J = 6.9Hz, 1H), 4.47 (ddd, J = 49.0, 9.3, 2.1 Hz, 1H), 3.97 (ddd, J = 36.4,14.6, 2.2 Hz, 1H), 3.54 (ddd, J = 16.2, 14.5, 9.3 Hz, 1H), 1.85 (d, J =7.0 Hz, 3H), 1.32 (d, J = 1.7 Hz, 6H) 4 1H NMR (400 MHz, Methanol-d4) δ8.79 (d, J = 2.2 Hz, 1H), 8.73 (s, 1H), 8.71 (d, J = 2.2 Hz, 1H), 8.09(d, J = 5.0 Hz, 1H), 8.07 (s, 1H), 7.26 (d, J = 5.1 Hz, 1H), 5.15 (q, J= 7.0 Hz, 1H), 4.46 (ddd, J = 49.0, 9.4, 2.2 Hz, 1H), 3.99 (ddd, J =36.3, 14.5, 2.1 Hz, 1H), 3.60-3.43 (m, 1H), 1.85 (d, J = 7.0 Hz, 3H),1.32 (d, J = 1.7 Hz, 6H). 5 1H NMR (400 MHz, Methanol-d4) δ 8.77 (t, J =1.8 Hz, 1H), 8.73 (d, J = 1.4 Hz, 1H), 8.68 (d, J = 2.0 Hz, 1H), 8.08(dd, J = 5.2, 1.4 Hz, 1H), 8.04 (d, J = 1.4 Hz, 1H), 7.23 (dd, J = 5.1,1.4 Hz, 1H), 5.05 (t, J = 6.9 Hz, 1H), 4.45 (ddd, J = 49.0, 9.3, 2.1 Hz,1H), 3.94 (ddd, J = 36.5, 14.6, 2.3 Hz, 1H), 3.52 (td, J = 15.2, 9.3 Hz,1H), 2.17 (p, J = 7.2 Hz, 2H), 1.29 (d, J = 1.6 Hz, 6H), 1.25 (td, J =7.4, 1.4 Hz, 3H). 6 1H NMR (400 MHz, Methanol-d4) δ 8.71 (d, J = 2.7 Hz,1H), 8.63 (d, J = 2.3 Hz, 1H), 8.56 (d, J = 2.3 Hz, 1H), 8.24 (s, 1H),7.93 (d, J = 4.8 Hz, 1H), 7.13 (d, J = 5.0 Hz, 1H), 4.80 (d, J = 6.3 Hz,1H), 4.43 (ddd, J = 49.0, 9.2, 2.4 Hz, 1H), 4.09-3.80 (m, 1H), 3.49(ddd, J = 15.8, 14.3, 9.7 Hz, 1H), 2.14 (p, J = 7.2 Hz, 2H), 1.29 (d, J= 1.8 Hz, 6H), 1.27-1.18 (m, 3H). 7 1H NMR (400 MHz, Methanol-d4) δ 8.78(d, J = 2.1 Hz, 1H), 8.69 (d, J = 2.2 Hz, 1H), 8.63 (s, 1H), 8.09 (d, J= 5.0 Hz, 1H), 7.96 (s, 1H), 7.24 (d, J = 5.1 Hz, 1H), 4.46 (ddd, J =49.1, 9.4, 2.2 Hz, 1H), 4.10-3.85 (m, 3H), 3.52 (ddd, J = 16.2, 14.5,9.4 Hz, 1H), 2.97 (t, J = 6.5 Hz, 2H), 1.31 (d, J = 1.7 Hz, 6H). 8 1HNMR (400 MHz, Methanol-d4) δ 8.78 (d, J = 2.2 Hz, 1H), 8.70 (d, J = 2.2Hz, 1H), 8.58 (s, 1H), 8.05 (d, J = 5.1 Hz, 1H), 7.93 (s, 1H), 7.24 (d,J = 5.1 Hz, 1H), 4.45 (ddd, J = 49.0, 9.3, 2.2 Hz, 1H), 3.97 (ddd, J =36.3, 14.6, 2.2 Hz, 1H), 3.74 (t, J = 7.1 Hz, 2H), 3.51 (ddd, J = 16.2,14.6, 9.3 Hz, 1H), 2.67 (t, J = 7.0 Hz, 2H), 2.13 (p, J = 7.0 Hz, 2H),1.31 (d, J = 1.7 Hz, 6H). 9 1H NMR (400 MHz, Methanol-d4) δ 8.78 (d, J =2.2 Hz, 1H), 8.77 (s, 1H), 8.70 (d, J = 2.2 Hz, 1H), 8.57 (s, 1H), 7.99(d, J = 5.1 Hz, 1H), 7.25 (d, J = 5.1 Hz, 1H), 4.46 (ddd, J = 49.1, 9.4,2.1 Hz, 1H), 3.96 (ddd, J = 36.5, 14.6, 2.1 Hz, 1H), 3.53 (ddd, J =16.1, 14.6, 9.4 Hz, 1H), 1.98 (s, 6H), 1.31 (d, J = 1.7 Hz, 6H). 10 1HNMR (400 MHz, Methanol-d4) δ 8.77 (d, J = 2.1 Hz, 1H), 8.73 (d, J = 2.2Hz, 1H), 8.69 (s, 1H), 8.50 (s, 1H), 8.04 (d, J = 5.1 Hz, 1H), 7.24 (d,J = 5.1 Hz, 1H), 4.43 (ddd, J = 49.0, 9.3, 2.1 Hz, 1H), 3.94 (ddd, J =36.3, 14.6, 2.1 Hz, 1H), 3.49 (ddd, J = 16.2, 14.6, 9.3 Hz, 1H),1.97-1.84 (m, 2H), 1.64-1.53 (m, 2H), 1.29 (d, J = 1.6 Hz, 6H).Biological Assays

Biological assays were conducted to measure activity against TNFα andIRAK4. As summarized in Table 3, the test compounds are inhibitors ofIRAK4.

IRAK4 Monocyte TNFα Cell Based Assay Procedure:

Cryopreserved human monocytes (Stem Cell Technologies) were thawed,diluted in RPMI with GlutaMAX™ (Gibco® 200 mM L-alanyl-L-glutamine) (10mM HEPES, 1×Pen-Strep, 55 μM ß-mercaptoethanol, 1 mM Sodium pyruvate)media containing 10% FBS to 0.125×10⁶ cells/ml and recovered at 37° C.for 2 hours. The cell suspension was then plated at a density of 5,000cells/well onto black 384 well Greiner clear bottom plates. Plates werepre-spotted with test compounds and serially diluted in DMSO where 40nL/well were delivered using the Echo 550 acoustic liquid dispenser(Labcyte®) for a final DMSO concentration of 0.1%. Plated cells weretreated with compound for 1 hour at 37° C. Cells were then stimulatedwith 50 pg/ml of LPS (Sigma) excluding outside columns of plate used forunstimulated cell control wells. Cells were incubated for an additional4 hours at 37° C. Cells were then spun out of the media and 5 μl ofsample were taken and analyzed for total TNFα content using the TR-FRETHuman TNFα detection system (CisBio). This system utilizes two labeledantibodies (cryptate and XL665) that bind to two different epitopes ofthe TNFα molecule and produce FRET signal proportional to theconcentration of TNFα in the sample. Detection antibodies are mixed50:50 and 5 μL were dispensed into each well. Plates were covered withclear seals and incubated at room temp overnight. The following morningplates were read using an Envision 2103 Multilabeled reader(PerkinElmer) with excitation/emission/FRET emission at 340 nm/615nm/665 nm, respectively. Fluorescence intensities at 615 nm and 665 nmemission wavelengths were expressed as a ratio (665 nm/615 nm). Percentof control was calculated as follows:%Control=100×(Ratio_(Sample)−Ratio_(0% stimulation))/(Ratio_(100% Stimulation)−Ratio_(0% Stimulation))where unstimulated cells (0% stimulation) were the negative control andstimulated cells (100% stimulation) were used as the positive control.IRAK4 Biochemical Assay Procedure:

IRAK4 enzyme (Carna Biosciences, Chuo-ku, Kobe, Japan) activity wasmeasured by detecting phosphorylated peptide substrate formation usingan antibody against the phosphorylated peptide substrate. This is atime-resolved fluorescence resonance energy transfer (TR-FRET)immunoassay, based on the STK1 KnEASE Assay (Cisbio, Bedford, Mass.).The assay was designed as a simple two-step, endpoint assay (a 5 μlenzyme reaction followed by 5 μl stop and detect Solution) performed inProxiPlate-384 Plus plates (Perkin Elmer, Waltham, Mass.).Staurosporine, a non-selective kinase inhibitor was used as a positivecontrol. Compounds diluted in DMSO were spotted into 384 well platesusing a Labcyte® Echo 550 Liquid Handling System prior to addition ofIRAK4 enzyme and peptide substrate. Reaction solutions were deliveredusing a Multi-Flo (Bio-Tek Instruments). The enzyme and peptide solutionwas incubated with compound for 15 minutes at room temp before thereaction was initiated by the addition of ATP. The standard 5l reactionmixture contained 500 μM ATP, 2 μM peptide (STK1 Peptide), 0.75 nM ofIRAK4 in reaction buffer (50 mM HEPES, pH 7.0, 0.02% NaN₃, 0.01% BSA,0.1 mM Orthovanadate, 5 mM MgCl₂, 0.025% NP-40, 1 mM DTT). After 120 minof incubation at room temperature, 5 μl of Stop and Detect Solution(1:100 Cryptate labeled anti-phosphorylated peptide antibody solutionand 125 nM Tracer in a 50 mM HEPES pH 7.0 detection buffer containingsufficient EDTA) was added. The plate was then further incubated for 60minutes at room temperature and read on Envision 2103 Multilabeledreader (PerkinElmer) with excitation/emission/FRET emission at 340nm/615 nm/665 nm, respectively. Fluorescence intensities at 615 nm and665 nm emission wavelengths were expressed as a ratio (665 nm/615 nm).Percentage of inhibition was calculated as below:%Inhibition=100×(Ratio_(Sample)−Ratio_(0% Inhibition))/(Ratio_(100% Inhibition)−Ratio_(0% Inhibition))The 0% inhibition value comes from control wells lacking inhibitor. The100% inhibition value comes from control wells containing a saturatingamount of known inhibitor staurosporine.Hepatic Stability:

Metabolic Stability in Cryopreserved Hepatocytes: Complete HT medium wasprepared by the addition of 1 mL Torpedo Antibiotic Mix to 45 mL ofInVitroGRO™ HT medium. Supplemented KHB medium consisted ofKrebsHenseleit buffer with amikacin (84 μg/mL), calcium chloride (1 mM),gentamicin (84 μg/mL), HEPES (20 mM), heptanoic acid (4.2 μM) and sodiumbicarbonate (28.5 mM) and the pH was adjusted to 7.4 at 37° C. using 1 MNaOH or 1 M HCl. The human cryopreserved hepatocytes were pooled fromten adult donors (Celsis, Lot: HBZ).

Vials containing cryopreserved hepatocytes were removed from liquidnitrogen and immediately immersed in a 37° C. water bath. The vials wereshaken gently until the contents had thawed and were then immediatelyemptied into 48 mL of pre warmed Complete HT Medium in a 50 mL conicaltube. Cells remaining in the vial were resuspended with 1.0 mL of prewarmed Complete HT Medium and added to the conical tube. The tube wascapped and then gently inverted several times to resuspend thehepatocytes. The cell suspension was centrifuged at 50×g at roomtemperature for 5 minutes and the supernatant discarded. The cell pelletwas loosened by gently swirling the centrifuge tube and Supplemented KHBmedium was added to obtain a target density of 2×10⁶ cells/mL. The totalcell count and the proportion of viable cells were determined by TrypanBlue dye exclusion using a hemocytometer.

For incubations, aliquots of hepatocyte suspension (250 μL containing500,000 cells) were added to 250 μL of 2 μM test compound or metabolicstability controls in supplemented KHB in duplicate wells in a 24-wellplate. Final concentration in the incubations were 1×10⁶ cells/mL and 1μM test compound. 7-Hydroxycoumarin and testosterone, compounds known tobe efficiently metabolized by hepatocytes, were used as positivecontrols in parallel incubations (2 μM final concentration of eachcompound). The incubation was carried out with gentle shaking at 37° C.under a humid atmosphere of 95% air/5% CO₂ (v/v). Aliquots (50 μL) wereremoved after 0, 1, 3, and 6 hours and added to 100 μL IS/Q quenchingsolution. After termination, 150 μL of water was added, the plates werecentrifuged at 3000×g for 10 min, and aliquots of the supernatant wereanalyzed on a Micromass Quattro Premier mass spectrometer coupled to anAgilent 1200 Series HPLC system with a Leap Technologies HTC PALautosampler as described below.

Liquid Chromatography-Mass Spectrometry: Quantification of test compoundand metabolic stability controls was performed by analyte/internalstandard peak area ratios (PAR) measured on a Micromass Quattro PremierXL tandem triple quadrupole mass spectrometer coupled to an Agilent 1200Series HPLC system with a Leap Technologies HTC PAL autosampler. Thecolumn used was a Phenomenex® MercuryMS™, Synergi Max-RP (100 Å poresize, 2.5 μm particle size, 20×2.0 mm). Mobile Phase A consisted of 0.2%(v/v) formic acid in 99% water/1% acetonitrile (v/v). Mobile Phase Bconsisted of 0.2% (v/v) formic acid in 5% water/95% acetonitrile (v/v).Elution was achieved by the following series of linear gradients:initial conditions of 0% B, holding for 30 s, then increasing to 100% Bover 90 s, and then returning to the initial conditions over 1 s. Thesystem was allowed to re-equilibrate for a minimum of 60 s betweeninjections. The sample injection volume was 10 μL.

LTP Plasma Protein Binding:

A stock solution of test compound in dimethyl sulfoxide (DMSO) having afinal concentration of 10 mM was prepared and used in all experiments.

Commercially available chemicals were obtained from Sigma-Aldrich (St.Louis, Mo.) and VWR (West Chester, Pa.). The cell culture medium (CCM)was Gibco Dulbecco's Modified Eagle Medium (DMEM) with 10% (v/v) fetalbovine serum.

Equilibrium dialysis Assay: Pooled plasma (from at least 3 males and 3females) was from human, beagle dog, Sprague-Dawley rat, cynomolgusmonkey, and rhesus monkey. Sodium EDTA was used as the anticoagulant.

Competitive equilibrium dialysis was conducted at 37° C. using humanplasma versus with CCM containing 10% of FBS, both sides of matrixspiked with sample at final concentrations of 2 μM. Prior to the study,dialysis membrane was soaked for approximately one hour in 0.133 Mphosphate buffer, pH 7.4. Spiked plasma (1 mL) and CCM (1 mL) wereplaced into opposite sides of the assembled dialysis cells. Forassessment of recovery, after the 24-hour equilibration period in a 37°C. water bath, plasma samples were drained into pre-weighedpolypropylene tubes containing 1 mL of CCM (without compound) and CCMsamples were drained into pre-weighed tubes containing 1 mL of relatedblank plasma. Post-dialysis plasma and CCM weights were measured andrecorded for calculations.

Liquid Chromatography-Mass Spectrometry:

The quantification of test compound was performed by analyte/internalstandard peak area ratios (PAR) measured on a Q-Exactive massspectrometer coupled to an Agilent 1260 Series HPLC system with a LeapTechnologies HTS PAL autosampler. Mobile Phase A consisted of 0.2% (v/v)formic acid in 99% water/1% acetonitrile (v/v). Mobile Phase B consistedof 0.2% (v/v) formic acid in 5% water/95% acetonitrile (v/v). The sampleinjection volume was 10 μL.

pK_(a) Determinations:

Sample Preparation: A stock solution of test compound in dimethylsulfoxide (DMSO) having a final concentration of 10 mM was prepared andused in all experiments. The DMSO stocks were thawed, spun, andsonicated in a 40° C. water bath to facilitate dissolution.

pK_(a) Analysis: The 10 mM DMSO stock solutions were diluted 100 foldwith 10 mM HCl for a final compound concentration of 100 μm and 1% DMSO.The compounds were then transferred into 24 consecutive wells of a 96well PCR plate for analysis with the aqueous method. For compounds thatdid not give high quality data in the aqueous method, the 10 mM DMSOstock solutions were diluted 100 fold with 2 mM HCl and methanol, suchthat the final concentration of methanol was 60%, compound concentrationwas 100 μm, and DMSO concentration was 1%. The compounds weretransferred into 24 consecutive wells of a 96 well plate for analysisusing the co-solvent method.

Analysis: All data was obtained using a pKa PRO Analyzer (AATI, Ames,Iowa). For the aqueous method, an electrophoretic separation isperformed in parallel across 24 different pH values, providing a directmeasure of overall compound charge vs. pH. The compounds are detected byUV at 228 nm. The average pH spacing between buffer points is 0.4 pHunits covering a typical pH range of 1.7-11.2.

The co-solvent method is suitable for analysis of compounds possessinglow aqueous solubility (typically a predicted intrinsic solubility of<10 μg/ml). The average pH spacing between buffer points is 0.4 pH unitscovering a pH range of 1.7-11.2. Four consecutive CE runs are performedfor each compound starting with 60% co-solvent buffers and decreasing to30% co-solvent buffers.

Norfloxacin is used as a daily performance-indicating standard.

Calculation of Results: The total number of pKa values is predicted byrelating mobility and compound molecular weight using pKa Estimator®software (AATI, Ames, Iowa).

Automated hERG Assay at Charles River—Cleveland (Formerly ChanTest)

The FASTPatch® Assay (Charles River) was used to examine the in vitroeffects of various compounds on the cloned hERG potassium channelencoded by the KCNH2 gene and stably expressed in HEK293T cells.Vehicle, test and control article formulations were prepared by dilutingDMSO stock solutions in HB-PS (HEPES-buffered physiological salinesolution), and were delivered to cells via the QPatch robot pipettingsystem to a final concentration of 0.3% DMSO. Test compound finalconcentrations of 0.3, 1, 3, 10 and 30 uM were applied to cells (n≥3,where n=the number of cells/concentration) in ascending order in atleast three minute intervals separated by solution exchange. Thepositive control, 50 nM Cisparide, was applied in the same manner. Cellmembrane currents were recorded at room temperature with up to 48parallel patch clamp amplifiers in the QPatch HT® or QPatch HTX® system,and only cells with validated whole-cell recordings (seal resistance≥200 MO and leak current ≤25% channel current) were used. Onset andblock of hERG current was measured using a stimulus voltage patternconsisting of a 500 ms prepulse to −40 mV, a 2-second activating pulseto +40 mV, followed by a 2-second test pulse to −40 mV. The pulsepattern was repeated continuously at 10-second intervals from a holdingpotential of −80 mV. TurboSol analysis for test compound solubility wasperformed for each concentration tested using a Nephelostar readermeasuring light scatter from a 635 nm laser source. Based on validationexperiments, light scatter above four times the background level wasconsidered an indication of the presence of particles in suspension.

Results from In Vitro Assays are presented in Table 3, below:

TABLE 3 IC₅₀ EC₅₀ Protein Adj. Human Hep. hERG HTRF TNF EC₅₀ TNFStability IC₅₀ compound (nM) (nM) (nM) (L/h/kg) pK_(a) (uM) A <1 23 5040.20 6.1 3.9 1 2 50 383 0.05 6.6 1.7 2 <1 19 232 0.13 5.1 >10 3 <1 14191 0.08 4.9 >30 4 2 115 5 1 60 6 5 267 7 164 8 <1 33 0.14 5.9 3.5 9 <149 0.26 4.8 10 <1 35 0.22

What is claimed is:
 1. A method of treating an inflammatory conditionselected from: rheumatoid arthritis (RA), inflammatory bowel disease(IBD), gout, Lyme disease, arthritis, psoriasis, pelvic inflammatorydisease, systemic lupus erythematosus (SLE), Sjogren's syndrome, or,Psoriasis, in a patient in need thereof, comprising administering tosaid patient a compound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, D ormethyl, R² is H, D or methyl, or R¹ and R², together with the carbonatoms to which they are attached, form cyclopropyl.
 2. The method ofclaim 1 wherein the condition is arthritis.
 3. The method of claim 2wherein the condition is RA.
 4. The method of claim 1 wherein thecondition is systemic lupus erythematosus.
 5. The method of claim 1wherein the condition is IBD.
 6. The method of claim of 1 wherein thecondition is pelvic inflammatory disease.
 7. The method of claim 1wherein the condition is Sjogren's syndrome.
 8. The method of claim 1wherein the condition is gout.
 9. The method of claim 1 wherein thecondition is Lyme disease.
 10. The method of claim 1 wherein thecondition is psoriasis.
 11. A method of treating an inflammatorycondition selected from rheumatoid arthritis (RA), inflammatory boweldisease (IBD), gout, Lyme disease, arthritis, psoriasis, pelvicinflammatory disease, systemic lupus erythematosus (SLE), or Sjogren'ssyndrome, in a patient in need thereof, comprising administering to saidpatient the compound

or a pharmaceutically acceptable salt thereof.
 12. The method of claim11 wherein the condition is arthritis.
 13. The method of claim 12wherein the condition is RA.
 14. The method of claim 11 wherein thecondition is systemic lupus erythematosus.
 15. The method of claim 11wherein the condition is IBD.
 16. The method of claim 11 wherein thecondition is pelvic inflammatory disease.
 17. The method of claim 11wherein the condition is Sjogren's syndrome.
 18. The method of claim 11wherein the condition is gout.
 19. The method of claim 11 wherein thecondition is Lyme disease.
 20. The method of claim 11 wherein thecondition is psoriasis.
 21. A method of treating an inflammatorycondition selected from rheumatoid arthritis (RA), inflammatory boweldisease (IBD), gout, Lyme disease, arthritis, psoriasis, pelvicinflammatory disease, systemic lupus erythematosus (SLE), or Sjogren'ssyndrome, in a patient in need thereof, comprising administering to saidpatient a pharmaceutical composition comprising the compound:

or a pharmaceutically acceptable salt thereof, together with at leastone pharmaceutically acceptable excipient.
 22. The method of claim 21wherein the condition is arthritis.
 23. The method of claim 22 whereinthe condition if RA.
 24. The method of claim 21 wherein the condition issystemic lupus erythematosus.
 25. The method of claim 21 wherein thecondition is IBD.
 26. The method of claim 21 wherein the condition ispelvic inflammatory disease.
 27. The method of claim 21 wherein thecondition is Sjogren's syndrome.
 28. The method of claim 21 wherein thecondition is gout.
 29. The method of claim 21 wherein the condition isLyme disease.
 30. The method of claim 21 wherein the condition ispsoriasis.